Benzene derivatives and pharmaceutical composition

ABSTRACT

A benzene derivative of the formula (I): ##STR1## wherein R 1  is hydrogen, C 1-6  -alkyl, C 1-6  -haloalkyl, --NH 2 , --NHR 21  ; R 2  is hydroxyl, --OR 22 , three- to seven-membered saturated cycloaliphatic amino optionally interrupted by one or more nitrogen, oxygen or sulfur atoms, --NHR 23 , --N(R 24 ) 2 , --NH 2  ; R 4  is hydrogen, C 1-6  -alkyl, or --C(═O)R 25  ; R 7  is --CO--, --SO 2  --; R 8  is --CO--, single bond; R 12  is --R 11  --R 5  ; R 11  is --N(R 5 )--, --NH--, --O--, --N(R 26 )--, --N(C(═O)R 27 )--, --N(C(═O)NH 2 )--, --N(C(═O)NHR 28 )--; R 13  is hydrogen, C 1-6  -alkyl, C 1-6  -haloalkyl, --NHC(═O) (CH 2 ) m  C 6  H 5 , --NHC(═O) R 29 , --NHC(═O)CH(C 6  H 5 ) 2 , --NH 2 , --NHR 30 , --(CH 2 ) n  C 6  H 5  ; Z is C, CH, N; A is CH, N; R 5  is hydrogen, --CH 2  C 6  H 4  COOH, --CH 2  C 6  H 4  COOR 31 , --CH 2  C 6  H 4  OH, --CH 2  C 6  H 4  OR 32 , --CH 2  C 6  H 4  NH 2 , --CH 2  C 6  H 4  N(R 33 ) 2 , --CH 2  C 6  H 4  -azole, --CH 2  C 6  H 4  NHR 34 , --CH 2  C 6  H 4  C 6  H 4  R 14  ; R 14  is azole, --COOH; R 21  to R 34  are independently C 1-6  -alkyl or C 1-6  -haloalkyl; m is 0 to 6; n is 0 to 6; t is 0 or 1, with the proviso that when Z is N, R 5  is hydrogen, --CH 2  C 6  H 4  COOH, --CH 2  C 6  H 4  COOR 31 , --CH 2  C 6  H 4  OH, --CH 2  C 6  H 4  OR 32 , --CH 2  C 6  H 4  NH 2 , --CH 2  C 6  H 4  N(R 33 ) 2 , --CH 2  C 6  H 4  -azole, or --CH 2  C 6  H 4  NHR 34 , or a salt thereof, and a pharmaceutical composition comprising said benzene derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier are disclosed.

This is a divisional of application Ser. No. 08/457,147 filed 1 Jun.1995 allowed.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel benzene derivative or a saltthereof, and a pharmaceutical composition, particularly, an agent fortreating a kidney disease, containing said benzene derivative or apharmaceutically acceptable salt thereof. Although the benzenederivative of the present invention exhibits substantially no or veryweak antagonism to the angiotensin II receptor subtype 1 whichparticipates in action to depress blood pressure, it can sufficientlyimprove a kidney disease.

2. Description of the Related Art

Recently, there is an increasing tendency of patients suffering fromrenal dysfunction. The reason is believed that a development of drugsappropriate to treat kidney diseases is behind with an increasing agedpopulation or changes in living environment. Therefore, the drugsappropriate to treat kidney diseases have been strongly desired.

More particularly, a method for treating lesions accompanying diseases,i.e., the nosotropic treatment., is mainly used as yet for kidneydiseases, such as nephritis, diabetic nephropathy or renal failure. Forexample, an antihypertensive, diuretic or anti-inflammatory agent, ordietary treatment, kinesitherapy or the like is mainly used. Becausekidney diseases are accompanied with hypertension and the hypertensionis believed to be one of factors aggravating kidney diseases, theantihypertensive agents are often used. Of the antihypertensive agents,the agents to inhibit production or function of angiotensin II areattempted in many cases. This is because that angiotensin II is believedto be a factor aggravating kidney diseases due to its activities toraise blood pressure and accelerate growth of interstitial cells in thekidney, and elimination of such a factor as much as possible is believedto improve the kidney diseases.

It is reported in J. Clin. Pharmacol., 30:155-158, 1990 that when theantihypertensive agent (such as enalapril or captoril), namely, theagent to inhibit the enzyme to convert angiotensin I to angiotensin IIwhich exhibits the activity to raise blood pressure (angiotensinconverting enzyme; ACE), i.e., the angiotensin converting enzymeinhibitor (ACEI), is used, blood pressure is lowered and the progress ofrenal dysfunction is improved. U.S. Pat. No. 5,071,867 suggests thatbecause the improvement of the renal dysfunction is observed in ratssuffering therefrom by administering the antihypertensive agent in anamount larger than that usually used to lower blood pressure, human willbecome endurable to a large dose if the dose is carefully and graduallyincreased, and to thereby enjoy the benefit of curing the renaldysfunction in human. On the other hand, it is pointed out in "SaishinIgaku (Latest Medicine)", 48: 1404-1409, 1993 that such agents have sideeffects such as dry-cough as their inherent properties, or are attendedwith danger to lower blood pressure and then cause acute renal failure,and therefore should be carefully administered.

Thereafter, an angiotensin II receptor antagonist (AGIIRA) was developedas a antihypertensive agent. Two kinds of the angiotensin II receptors,the subtype 1 and the subtype 2, are known at the present. Although thefunctions of the subtype 2 are not sufficiently elucidated, the subtype1 is known to participate in blood pressure. Therefore, the subtype 1receptor antagonist is a target of the development of theantihypertensive agent.

As the compounds which are antihypertensive agents exhibiting a strongantagonizing activity to the angiotensin II receptor, and at the sametime, are examined for their action to kidney diseases, the imidazolederivative, 2-butyl-4-chloro-5-(hydroxymethyl)-1-2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!imidazole (Dup753 or MK954) isknown. When the imidazole derivative was administered to renaldysfunction model rats, it was effective against proteinuria andglomerulosclerosis, but at the same time the reduction of blood pressureaccompanied (j. Clinical Invest., 90: 766-771, 1992). Further, when theabove imidazole derivative was administered to hyperlipemia model rats,the kidney disease was improved in a lower dose without practical effectto blood pressure, but an evident reduction of blood pressure wasobserved at a large dose more effective against the kidney disease(Nephron, 65: 426-432, 1993).

Further, compounds having the structures similar to that of the aboveimidazole derivative are disclosed in Japanese Unexamined PatentPublication No. 63-23868, and US Pat. Nos. 5,153,197, 5,128,355 and5,155,118. Japanese Unexamined Patent Publication No. 63-23868 disclosesthat such compounds are effective against hypertension and congestiveheart failure. U.S. Pat. No. 5,153,197 discloses that such compounds areeffective against hypertension. U.S. Pat. No. 5,128,355 discloses thatsuch compounds are effective against heart failure. U.S. Pat. No.5,155,118 discloses that such compounds are effective against renalfailure caused by non-steroid anti-inflammatory agent. However, all theimidazole derivatives disclosed in said Japanese Unexamined PatentPublication and US Patents are characterized by a strong angiotensin IIreceptor antagonism, and have an activity to lower blood pressure.

EP 058829A2 and EP 0475206A2 disclose the compounds having a benzeneskeleton and its application to kidney diseases. However, the benzenecompounds are characterized by a strong angiotensin II receptorantagonism accompanied by the lowering function of blood pressure.Further, it is reported in J. Pharmacol. Experimental Therapeutics, 267:657-663, 1993 that when one of the benzene analogues, 2- N-propyl-N-2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!amino!pyridine-3-carboxylicacid (A-81988), was administered to kidney disease model rats,proteinuria was improved, but at the same time, the reduction of bloodpressure was observed. The above benzene analogues exhibits the functionto lower blood pressure due to the strong angiotensin II receptorantagonism, and therefore, there is a fear of acute renal failure or thelike when administered to the person suffering from kidney diseases.

As above, hitherto, drugs having the function to strongly lower bloodpressure were basically desired in the treatment of the kidney diseasesby the antihypertensive agent. In the kidney disease, the hypertensionis an important symptom to be improved. However, mere lowering of bloodpressure is not favorable. It is important to maintain appropriate bloodpressure. Thus, it is necessary to adjust blood pressure by combiningthe kinds and the doses of the antihypertensive agents in view of thesymptom. However, continuous treatment with a sufficient dose is desiredfor the kidney diseases per se. Therefore, so long as a conventionalantihypertensive agent is used, it is fundamentally impossible toappropriately adjust blood pressure and at the same time to effectivelycure the kidney disease by the sole antihypertensive agent. One of suchproblems is, for example, the above acute renal failure caused by theantihypertensive agent used.

SUMMARY OF THE INVENTION

The inventors of the present invention engaged in intensive studies tofind the compounds having the properties which were completely unknownin the past, namely the compounds sufficiently effective in improvementof the renal dysfunction without any function to blood pressure, and asa result, found novel benzene derivatives which are sufficientlyeffective in improvement of the renal dysfunction while the antagonismthereof to the angiotensin II receptor subtype 1 is one-hundredth(1/100) to one-thousandth (1/1000) or less as large as that of theconventional antagonist having a standard activity as a antihypertensiveagent. The present invention is based on the finding.

Accordingly, the present invention relates to a benzene derivative ofthe formula (I): ##STR2## wherein R¹ is a hydrogen atom, alkyl of 1 to 6carbon atoms, haloalkyl of 1 to 6 carbon atoms, --NH₂, or --NHR²¹ group;R² is a hydroxyl, --OR²², three- to seven-membered saturatedcycloaliphatic amino group which may be interrupted by one or morenitrogen, oxygen or sulfur atoms, --NHR²³, --N(R²⁴)₂, or --NH₂ group; R⁴is a hydrogen atom, alkyl of 1 to 6 carbon atoms, or --C(═O)R²⁵ group;R⁷ is a --CO-- or --SO₂ --; R⁸ is a --CO-- or single bond; R¹² is --R¹¹--R⁵ ; R¹¹ is --N(R⁵)--, --NH--, --O--, --N(R²⁶)--, --N(C(═O)R²⁷)--,--N(C(═O)NH₂)--, or --N(C(═O)NHR²⁸)--; R¹³ is a hydrogen atom, alkyl of1 to 6 carbon atoms, haloalkyl of 1 to 6 carbon atoms,--NHC(═O)(CH₂)_(m) C₆ H₅, --NHC(═O)R²⁹, --NHC(═O)CH(C₆ H₅)₂, --NH₂,--NHR³⁰, or --(CH₂)_(n) C₆ H₅ ; Z is C, CH, or N; A is CH or N; R⁵ is ahydrogen atom, --CH₂ C₆ H₄ COOH, --CH₂ C₆ H₄ COOR³¹, --CH₂ C₆ H₄ OH,--CH₂ C₆ H₄ OR³², --CH₂ C₆ H₄ NH₂, --CH₂ C₆ H₄ N(R³³)₂, --CH₂ C₆ H₄-azole, --CH₂ C₆ H₄ NHR³⁴, or --CH₂ C₆ H₄ C₆ H₄ R¹⁴ group; R¹⁴ is anazole or --COOH group; R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸, R²⁹, R³⁰,R³¹, R³², R³³, and R³⁴, are independently an alkyl of 1 to 6 carbonatoms or haloalkyl group of 1 to 6 carbon atoms; m is 0 or an integer of1 to 6; n is 0 or an integer of 1 to 6; t is 0 or 1, with the provisothat when Z is N, R⁵ is a hydrogen atom, --CH₂ C₆ H₄ COOH, --CH₂ C₆ H₄COOR³¹, --CH₂ C₆ H₄ OH, --CH₂ C₆ H₄ OR³², --CH₂ C₆ H₄ NH₂, --CH₂ C₆ H₄N(R³³)₂, --CH₂ C₆ H₄ -azole, or --CH₂ C₆ H₄ NHR³⁴ group, or a saltthereof.

Further, the present invention relates to a pharmaceutical compositioncomprising a benzene derivative of the formula (I) or a pharmaceuticallyacceptable salt thereof and a pharmaceutically acceptable carrier ordiluent.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The term "alkyl" as used herein includes straight-chain and branchedalkyl groups, for example, an alkyl group of 1 to 4 carbon atoms, suchas methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, s-butyl ort-butyl; an alkyl group of 1 to 5 carbon atoms, such as those asmentioned above, n-pentyl, i-pentyl, neopentyl, t-pentyl, 1-methylbutyl,2-methylbutyl, 1,2-dimethylpropyl or 1-ethylpropyl; and an alkyl groupof 1 to 6 carbon atoms, such as those as mentioned above, n-hexyl,i-hexyl or 2-ethylbutyl.

The haloalkyl group of 1 to 6 carbon atoms is the above alkyl group of 1to 6 carbon atoms substituted with 1 to 13 halogen atoms as mentionedabove. The halogen atom is, for example, a chlorine, bromine, fluorineor iodine atom. The preferred haloalkyl group is, for example, atrifluoromethyl, pentafluoroethyl, or 4,4,4-trifluorobutyl.

The azole group is a 5-membered cyclic group containing 2 to 4heteroatoms, such as a nitrogen, oxygen or sulfur atom, such as a groupof imidazole, oxazole, thiazole, pyrazole, isoxazole, isothiazole,triazole, oxadiazole, thiadiazole, tetrazole, oxatriazole orthiatriazole. The preferred azole group is a tetrazole group.

The three- to seven-membered saturated cycloaliphatic amino group is analkyleneamino group which may be optionally interrupted by one or moreheteroatoms such as nitrogen, oxygen or sulfur atoms, for example,1-azetidinyl, 1-pyrrolidinyl, piperidino, morpholino, thiomorpholino, or1-piperazinyl group.

The compound of the formula (I) wherein R¹ is a hydrogen atom, alkyl of1 to 5 carbon atoms, haloalkyl of 1 to 5 carbon atoms, or --NHR²¹ group;R² is a hydroxyl, --OR²², three- to six-membered saturatedcycloaliphatic amino group which may be interrupted by one or morenitrogen, oxygen or sulfur atoms, --NHR²³, --N(R²⁴)₂, or --NH₂ group; R⁴is a hydrogen atom, alkyl of 1 to 4 carbon atoms, or --C(═O)R²⁵ group;R⁷ is a --CO-- or --SO₂ --; R⁸ is a --CO-- or single bond; R¹² is --R¹¹--R⁵ ; R¹¹ is --N(R⁵)--, --NH--, --O--, --N(R²⁶)--, --N(C(═O)R₂₇)--,--N(C(═O)NH₂)--, or --N(C(═O)NHR²⁸)--; R¹³ is a hydrogen atom, alkyl of1 to 4 carbon atoms, haloalkyl of 1 to 4 carbon atoms,--NHC(═O)(CH₂)^(m) C⁶ H₅, --NHC(═O)R²⁹, --NHC(═O)CH(C₆ H₅)₂, --NH₂,--NHR³⁰, or --(CH₂)^(n) C₆ H₅ ; Z is C, CH, or N; A is CH or N; R⁵ is ahydrogen atom, --CH₂ C₆ H₄ COOH, --CH₂ C₆ H₄ COOR³¹, --CH₂ C₆ H₄ OH,--CH₂ C₆ H₄ OR³², --CH₂ C₆ H₄ NH₂, --CH₂ C₆ H₄ N(R³³)₂, --CH₂ C₆ H₄-azole, --CH₂ C₆ H₄ NHR³⁴, or --CH₂ C₆ H₄ C₆ H₄ R¹⁴ group; R¹⁴ is an1H-tetrazole or --COOH group; R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, R²⁷, R²⁸,R²⁹, R³⁰, R³¹, R³², R³³, and R³⁴, are independently an alkyl of 1 to 4carbon atoms or haloalkyl group of 1 to 4 carbon atoms; m is 0 or aninteger of 1 to 4; n is 0 or an integer of 1 to 4; t is 0 or 1, with theproviso that when Z is N, R⁵ is a hydrogen atom, --CH₂ C₆ H₄ COOH, --CH₂C₆ H₄ COOR³¹, --CH₂ C₆ H₄ OH, --CH₂ C₆ H₄ OR³², --CH₂ C₆ H₄ NH₂, --CH₂C₆ H₄ N(R³³)₂, --CH₂ C₆ H₄ -azole, or --CH₂ C₆ H₄ NHR³⁴ group, or a saltthereof is preferable.

The compound of the formula (I) wherein R⁵ is --CH₂ C₆ H₄ COOH, or asalt thereof is more preferable.

The compound of the formula (I) wherein R⁵ is --CH₂ C₆ H₄ -4-COOH, or asalt thereof is most preferable.

The salt of the compound of the present invention includes a salt withan inorganic or organic acid or a salt with an inorganic or organicbase, preferably a pharmaceutically acceptable salt. As an acid additivesalt, there may be mentioned, for example, hydrochloride, sulfate,methanesulfonate or p-toluenesulfonate; a salt with a dicarboxylic acid,such as oxalic, malonic, succinic, maleic or fumaric acid; or a saltwith a monocarboxylic acid, such as acetic, propionic or butyric acid.The inorganic base suitable to form a salt of the compound of thepresent invention is, for example, a hydroxide, carbonate or bicarbonateof ammonium, sodium, lithium, calcium, magnesium or aluminum. As thesalt with the organic base, there may be mentioned, for example, a saltwith a mono-, di- or tri-alkylamine, such as methylamine, dimethylamineor triethylamine; a salt with a mono-, di- or tri-hydroxyalkylamine,guanidine, N-methylglucosamine or amino acid salt.

As the typical examples of the compounds according to the presentinvention, the structures of Compounds No. 1 to 717 are shown in thefollowing Tables 1 to 21. The compounds listed in the following Tablesare sometimes referred to the numbers in the following Tables. In thefollowing Tables, Me is methyl, Et is ethyl, Pr is propyl, Bu is butyl,Pen is pentyl, Hex is hexyl, Ph is phenyl, CN₄ H is 1H-tetrazol-5-yl, SBis single bond, NC₄ H₈ O is morpholino, NC₄ H₈ S is thiomorpholino, NC₅H₁₀ is piperidino, NC₄ H₈ is 1-pyrrolidinyl, NC₃ H₆ is 1-azetidinyl, N₂C₄ H₉ is 1-piperazinyl, CH₂ PhPh-2-CN₄ H is 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl, CO is carbonyl, and Ph-4- is 4-substitutedphenylene.

                                      TABLE 1                                     __________________________________________________________________________    No.                                                                              R.sup.1                                                                            A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12  R.sup.13                                     __________________________________________________________________________     1 nBu  N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                             2 nBu  N C NC.sub.3 H.sub.8                                                                   H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                             3 nBu  N C NC.sub.4 H.sub.8                                                                   H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                             4 nBu  N C NC.sub.5 H.sub.10                                                                  H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                             5 nBu  N C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                             6 nBu  N C NC.sub.4 H.sub.8 S                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                             7 nBu  N C NH.sub.2                                                                           H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                             8 nBu  N C NHMe H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                             9 nBu  N C NHEt H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            10 nBu  N C NMe.sub.2                                                                          H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            11 nBu  N C NEt.sub.2                                                                          H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            12 nBu  N C OH   H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            13 nBu  N C OMe  H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            14 nBu  N C OEt  H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            15 H    N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            16 Me   N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            17 Et   N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            18 nPr  N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            19 nPen N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            20 nHex N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            21 MeNH N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            22 EtNH N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            23 nPrNH                                                                              N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            24 nBuNH                                                                              N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            25 nPenNH                                                                             N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            26 Et   N C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            27 nHex N C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            28 nPenNH                                                                             N C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            29 Et   N C NC.sub.4 H.sub.8                                                                   H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            30 nHex N C NC.sub.4 H.sub.8                                                                   H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            31 nPenNH                                                                             N C NC.sub.4 H.sub.8                                                                   H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            32 Et   N C NEt.sub.2                                                                          H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            33 nHex N C NEt.sub.2                                                                          H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            34 nPenNH                                                                             N C NEt.sub.2                                                                          H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            35 Et   N C OH   H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    No.                                                                              R.sup.1                                                                            A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12  R.sup.13                                     __________________________________________________________________________    36 nHex N C OH   H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            37 nPenNH                                                                             N C OH   H CO                                                                              CO                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            38 Et   N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            39 nBu  N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            40 nHex N C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            41 nPen N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            42 nPen N C NC.sub.3 H.sub.6                                                                   Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            43 nPen N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            44 nPen N C NC.sub.5 H.sub.10                                                                  Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            45 nPen N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            46 nPen N C NC.sub.4 H.sub.8 S                                                                 Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            47 nPen N C NH.sub.2                                                                           Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            48 nPen N C NHMe Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            49 nPen N C NHEt Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            50 nPen N C NMe.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            51 nPen N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            52 nPen N C OH   Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            53 nPen N C OMe  Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            54 nPen N C OEt  Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            55 H    N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            56 Me   N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            57 Et   N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            58 nPr  N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            59 nBu  N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            60 nHex N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            61 Et   N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            62 nHex N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            63 Et   N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            64 nHex N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            65 Et   N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            66 nHex N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            67 Et   N C OH   Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            68 nHex N C OH   Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            69 Et   N C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            70 H    CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                    H                                            __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    No.                                                                              R.sup.1                                                                          A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12     R.sup.13                                    __________________________________________________________________________     71                                                                              Me CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            72                                                                              Et CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            73                                                                              nPr                                                                              CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            74                                                                              nBu                                                                              CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            75                                                                              nPen                                                                             CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            76                                                                              nPen                                                                             CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            77                                                                              nPen                                                                             CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            78                                                                              nPen                                                                             CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            79                                                                              nPen                                                                             CH                                                                              C OH   H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            80                                                                              Me CH                                                                              C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            81                                                                              Et CH                                                                              C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            82                                                                              H  CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            83                                                                              H  CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            84                                                                              H  CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            85                                                                              H  CH                                                                              C OH   H CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            86                                                                              Me CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            87                                                                              Me CH                                                                              C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            88                                                                              Me CH                                                                              C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            89                                                                              Me CH                                                                              C OH   Me                                                                              CO                                                                              SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                            90                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            91                                                                              -- --                                                                              CH                                                                              NC.sub.3 H.sub.6                                                                   --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            92                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            93                                                                              -- --                                                                              CH                                                                              NC.sub.5 H.sub.10                                                                  --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            94                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 S                                                                 --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            95                                                                              -- --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            96                                                                              -- --                                                                              CH                                                                              NH.sub.2                                                                           --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            97                                                                              -- --                                                                              CH                                                                              NHMe --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            98                                                                              -- --                                                                              CH                                                                              NHEt --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            99                                                                              -- --                                                                              CH                                                                              NMe.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                           100                                                                              -- --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                           101                                                                              -- --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                           102                                                                              -- --                                                                              CH                                                                              OMe  --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                           103                                                                              -- --                                                                              CH                                                                              OEt  --                                                                              CO                                                                              --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                           104                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                           105                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                           __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12      R.sup.13                                    __________________________________________________________________________    106                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                           107                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                           108                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                           109                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                           110                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                           111                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                           112                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                           113                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                           114                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                           115                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                           116                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                           117                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                           118                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                           119                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                           120                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                           121                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                           122                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                           123                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                           124                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                           125                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                           126                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                           127                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                           128                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                           129                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           130                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           131                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           132                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           133                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           134                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           135                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           136                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           137                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           138                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           139                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           140                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12      R.sup.13                                    __________________________________________________________________________    141                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           142                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           143                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           144                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           145                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           146                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           147                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           148                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           149                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           150                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           151                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           152                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           153                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           154                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           155                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           156                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           157                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           158                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                           159                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO                                                                              --                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                           160                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           161                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           162                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           163                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           164                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           165                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           166                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           167                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           168                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           169                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           170                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           171                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           172                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           173                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           174                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           175                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           __________________________________________________________________________

                                      TABLE 6                                     __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12     R.sup.13                                     __________________________________________________________________________    176                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                  H                                            177                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                  H                                            178                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                  H                                            179                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                  H                                            180                                                                              --                                                                              --                                                                              CH                                                                              N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO                                                                              --                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                  H                                            181                                                                              --                                                                              --                                                                              CH                                                                              NC.sub.4 H.sub.8                                                                   --                                                                              CO                                                                              --                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                  H                                            182                                                                              --                                                                              --                                                                              CH                                                                              NEt.sub.2                                                                          --                                                                              CO                                                                              --                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                  H                                            183                                                                              --                                                                              --                                                                              CH                                                                              OH   --                                                                              CO                                                                              --                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                  H                                            184                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            185                                                                              Me                                                                              N C NC.sub.3 H.sub.6                                                                   Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            186                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            187                                                                              Me                                                                              N C NC.sub.5 H.sub.10                                                                  Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            188                                                                              Me                                                                              N C NC.sub.4 H.sub.8 S                                                                 Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            189                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            190                                                                              Me                                                                              N C NH.sub.2                                                                           Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            191                                                                              Me                                                                              N C NHMe Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            192                                                                              Me                                                                              N C NHEt Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            193                                                                              Me                                                                              N C NMe.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            194                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            195                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            196                                                                              Me                                                                              N C OMe  Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            197                                                                              Me                                                                              N C OEt  Me                                                                              CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            198                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                            199                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                            200                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                H                                            201                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                               H                                            202                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                               H                                            203                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                            204                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                            205                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                            206                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                            207                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                            208                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                            209                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                            210                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                            __________________________________________________________________________

                                      TABLE 7                                     __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12      R.sup.13                                    __________________________________________________________________________    211                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                           212                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                           213                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                           214                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                           215                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                           216                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                           217                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                           218                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                           219                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                           220                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                           221                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                           222                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                           223                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           224                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           225                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           226                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           227                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           228                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           229                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           230                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           231                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           232                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           233                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           234                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           235                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           236                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           237                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           238                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           239                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           240                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           241                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           242                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           243                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           244                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           245                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           __________________________________________________________________________

                                      TABLE 8                                     __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12      R.sup.13                                    __________________________________________________________________________    246                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           247                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           248                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           249                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           250                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           251                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           252                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                           253                                                                              Me                                                                              N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO                                                                              SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                           254                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           255                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           256                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           257                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           258                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           259                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           260                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           261                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           262                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           263                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           264                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           265                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           266                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           267                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           268                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           269                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           270                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                           271                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                           272                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                           273                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                           274                                                                              Me                                                                              N C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO                                                                              SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                           275                                                                              Me                                                                              N C NC.sub.4 H.sub.8                                                                   Me                                                                              CO                                                                              SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                           276                                                                              Me                                                                              N C NEt.sub.2                                                                          Me                                                                              CO                                                                              SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                           277                                                                              Me                                                                              N C OH   Me                                                                              CO                                                                              SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                           278                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                           279                                                                              H CH                                                                              C NC.sub.3 H.sub.6                                                                   H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                           280                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                           __________________________________________________________________________

                                      TABLE 9                                     __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12     R.sup.13                                     __________________________________________________________________________    281                                                                              H CH                                                                              C NC.sub.5 H.sub.10                                                                  H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            282                                                                              H CH                                                                              C NC.sub.4 H.sub.8 S                                                                 H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            283                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            284                                                                              H CH                                                                              C NH.sub.2                                                                           H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            285                                                                              H CH                                                                              C NHMe H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            286                                                                              H CH                                                                              C NHEt H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            287                                                                              H CH                                                                              C NMe.sub.2                                                                          H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            288                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            289                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            290                                                                              H CH                                                                              C OMe  H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            291                                                                              H CH                                                                              C OEt  H CO                                                                              SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                            292                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                            293                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                            294                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                H                                            295                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                               H                                            296                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                               H                                            297                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                            298                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                            299                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                            300                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                            301                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                            302                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                            303                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                            304                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                            305                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                H                                            306                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                H                                            307                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                H                                            308                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                H                                            309                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                               H                                            310                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                               H                                            311                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                               H                                            312                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                               H                                            313                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                               H                                            314                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                               H                                            315                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                               H                                            __________________________________________________________________________

                                      TABLE 10                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12      R.sup.13                                    __________________________________________________________________________    316                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                           317                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           318                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           319                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           320                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           321                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           322                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           323                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           324                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           325                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                           326                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           327                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           328                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           329                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                           330                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           331                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           332                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           333                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                           334                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           335                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           336                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           337                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                           338                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           339                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           340                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           341                                                                              H CH                                                                              C OH   H CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                           342                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           343                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                           344                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                           345                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                           346                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                           347                                                                              H CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO                                                                              SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                           348                                                                              H CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                            H CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           349                                                                              H CH                                                                              C NC.sub.4 H.sub.8                                                                   H CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           350                                                                              H CH                                                                              C NEt.sub.2                                                                          H CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                           __________________________________________________________________________

                                      TABLE 11                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A  Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                          R.sup.8                                                                         R.sup.12      R.sup.13                                  __________________________________________________________________________    351                                                                              H CH C OH   H CO SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         352                                                                              H CH C N.sub.2 C.sub.4 H.sub.9                                                            H CO SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         353                                                                              H CH C NC.sub.4 H.sub.8                                                                   H CO SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         354                                                                              H CH C NEt.sub.2                                                                          H CO SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         355                                                                              H CH C OH   H CO SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         356                                                                              H CH C N.sub.2 C.sub.4 H.sub.9                                                            H CO SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                         357                                                                              H CH C NC.sub.4 H.sub.8                                                                   H CO SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                         358                                                                              H CH C NEt.sub.2                                                                          H CO SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                         359                                                                              H CH C OH   H CO SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                         360                                                                              H CH C N.sub.2 C.sub.4 H.sub.9                                                            H CO SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                         361                                                                              H CH C NC.sub.4 H.sub.8                                                                   H CO SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                         362                                                                              H CH C NEt.sub.2                                                                          H CO SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                         363                                                                              H CH C OH   H CO SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                         364                                                                              H CH C N.sub.2 C.sub.4 H.sub.9                                                            H CO SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                         365                                                                              H CH C NC.sub.4 H.sub.8                                                                   H CO SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                         366                                                                              H CH C NEt.sub.2                                                                          H CO SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                         367                                                                              H CH C OH   H CO SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                         368                                                                              H CH C N.sub.2 C.sub.4 H.sub.9                                                            H CO SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                         369                                                                              H CH C NC.sub.4 H.sub.8                                                                   H CO SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                         370                                                                              H CH C NEt.sub.2                                                                          H CO SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                         371                                                                              H CH C OH   H CO SB                                                                              N(nHex)CH.sub.2 2Ph-4-COOH                                                                  H                                         372                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         373                                                                              Me                                                                              CH C NC.sub.3 H.sub.6                                                                   Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         374                                                                              Me                                                                              CH C NC.sub.4 H.sub.8                                                                   Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         375                                                                              Me                                                                              CH C NC.sub.5 H.sub.10                                                                  Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         376                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 S                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         377                                                                              Me                                                                              CH C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         378                                                                              Me                                                                              CH C NH.sub.2                                                                           Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         379                                                                              Me                                                                              CH C NHMe Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         380                                                                              Me                                                                              CH C NHEt Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         381                                                                              Me                                                                              CH C NMe.sub.2                                                                          Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         382                                                                              Me                                                                              CH C NEt.sub.2                                                                          Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         383                                                                              Me                                                                              CH C OH   Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         384                                                                              Me                                                                              CH C OMe  Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         385                                                                              Me                                                                              CH C OEt  Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         __________________________________________________________________________

                                      TABLE 12                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A  Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                          R.sup.8                                                                         R.sup.12      R.sup.13                                  __________________________________________________________________________    386                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                         387                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         388                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         389                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         390                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         391                                                                              Me                                                                              CH C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                         392                                                                              Me                                                                              CH C NC.sub.4 H.sub.8                                                                   Me                                                                              CO SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                         393                                                                              Me                                                                              CH C NEt.sub.2                                                                          Me                                                                              CO SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                         394                                                                              Me                                                                              CH C OH   Me                                                                              CO SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                         395                                                                              Me                                                                              CH C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         396                                                                              Me                                                                              CH C NC.sub.4 H.sub.8                                                                   Me                                                                              CO SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         397                                                                              Me                                                                              CH C NEt.sub.2                                                                          Me                                                                              CO SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         398                                                                              Me                                                                              CH C OH   Me                                                                              CO SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         399                                                                              Me                                                                              CH C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         400                                                                              Me                                                                              CH C NC.sub.4 H.sub.8                                                                   Me                                                                              CO SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         401                                                                              Me                                                                              CH C NEt.sub.2                                                                          Me                                                                              CO SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         402                                                                              Me                                                                              CH C OH   Me                                                                              CO SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         403                                                                              Me                                                                              CH C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         404                                                                              Me                                                                              CH C NC.sub.4 H.sub.8                                                                   Me                                                                              CO SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         405                                                                              Me                                                                              CH C NEt.sub.2                                                                          Me                                                                              CO SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         406                                                                              Me                                                                              CH C OH   Me                                                                              CO SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         407                                                                              Me                                                                              CH C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         408                                                                              Me                                                                              CH C NC.sub.4 H.sub.8                                                                   Me                                                                              CO SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         409                                                                              Me                                                                              CH C NEt.sub.2                                                                          Me                                                                              CO SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         410                                                                              Me                                                                              CH C OH   Me                                                                              CO SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         411                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         412                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         413                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         414                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         415                                                                              Me                                                                              CH C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         416                                                                              Me                                                                              CH C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         417                                                                              Me                                                                              CH C NC.sub.4 H.sub.8                                                                   Me                                                                              CO SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         418                                                                              Me                                                                              CH C NEt.sub.2                                                                          Me                                                                              CO SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         419                                                                              Me                                                                              CH C OH   Me                                                                              CO SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         420                                                                              Me                                                                              CH C N.sub.2 C.sub.4 H.sub.9                                                            Me                                                                              CO SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         __________________________________________________________________________

                                      TABLE 13                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A Z R.sup.2                                                                             R.sup.4                                                                         R.sup.7                                                                         R.sup.8                                                                         R.sup.12       R.sup.13                                  __________________________________________________________________________    421                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8                                                                    Me                                                                              CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                                H                                         422                                                                              Me                                                                              CH                                                                              C NEt.sub.2                                                                           Me                                                                              CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                                H                                         423                                                                              Me                                                                              CH                                                                              C OH    Me                                                                              CO                                                                              SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                                H                                         424                                                                              Me                                                                              CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                             Me                                                                              CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                                H                                         425                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8                                                                    Me                                                                              CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                                H                                         426                                                                              Me                                                                              CH                                                                              C NEt.sub.2                                                                           Me                                                                              CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                                H                                         427                                                                              Me                                                                              CH                                                                              C OH    Me                                                                              CO                                                                              SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                                H                                         428                                                                              Me                                                                              CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                             Me                                                                              CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         429                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8                                                                    Me                                                                              CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         430                                                                              Me                                                                              CH                                                                              C NEt.sub.2                                                                           Me                                                                              CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         431                                                                              Me                                                                              CH                                                                              C OH    Me                                                                              CO                                                                              SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         432                                                                              Me                                                                              CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                             Me                                                                              CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                               H                                         433                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8                                                                    Me                                                                              CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                               H                                         434                                                                              Me                                                                              CH                                                                              C NEt.sub.2                                                                           Me                                                                              CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                               H                                         435                                                                              Me                                                                              CH                                                                              C OH    Me                                                                              CO                                                                              SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                               H                                         436                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8 O                                                                  Me                                                                              CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                      H                                         437                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8 O                                                                  Me                                                                              CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                      H                                         438                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8 O                                                                  Me                                                                              CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                     H                                         439                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8 O                                                                  Me                                                                              CO                                                                              SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                     H                                         440                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8 O                                                                  Me                                                                              CO                                                                              SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                    H                                         441                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8 O                                                                  Me                                                                              CO                                                                              SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                    H                                         442                                                                              Me                                                                              CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                             Me                                                                              CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                      H                                         443                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8                                                                    Me                                                                              CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                      H                                         444                                                                              Me                                                                              CH                                                                              C NEt.sub.2                                                                           Me                                                                              CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                      H                                         445                                                                              Me                                                                              CH                                                                              C OH    Me                                                                              CO                                                                              SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                      H                                         446                                                                              Me                                                                              CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                             Me                                                                              CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                      H                                         447                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8                                                                    Me                                                                              CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                      H                                         448                                                                              Me                                                                              CH                                                                              C NEt.sub.2                                                                           Me                                                                              CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                      H                                         449                                                                              Me                                                                              CH                                                                              C OH    Me                                                                              CO                                                                              SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                      H                                         450                                                                              Me                                                                              CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                             Me                                                                              CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                     H                                         451                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8                                                                    Me                                                                              CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                     H                                         452                                                                              Me                                                                              CH                                                                              C NEt.sub.2                                                                           Me                                                                              CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                     H                                         453                                                                              Me                                                                              CH                                                                              C OH    Me                                                                              CO                                                                              SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                     H                                         454                                                                              Me                                                                              CH                                                                              C N.sub.2 C.sub.4 H.sub.9                                                             Me                                                                              CO                                                                              SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                     H                                         455                                                                              Me                                                                              CH                                                                              C NC.sub.4 H.sub.8                                                                    Me                                                                              CO                                                                              SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                     H                                         __________________________________________________________________________

                                      TABLE 14                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A  Z R.sup.2                                                                             R.sup.4                                                                         R.sup.7                                                                          R.sup.8                                                                         R.sup.12     R.sup.13                                  __________________________________________________________________________    456                                                                              Me                                                                              CH C NEt.sub.2                                                                           Me                                                                              CO SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                   H                                         457                                                                              Me                                                                              CH C OH    Me                                                                              CO SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                   H                                         458                                                                              Me                                                                              CH C N.sub.2 C.sub.4 H.sub.9                                                             Me                                                                              CO SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                  H                                         459                                                                              Me                                                                              CH C NC.sub.4 H.sub.8                                                                    Me                                                                              CO SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                  H                                         460                                                                              Me                                                                              CH C NEt.sub.2                                                                           Me                                                                              CO SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                  H                                         461                                                                              Me                                                                              CH C OH    Me                                                                              CO SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                  H                                         462                                                                              Me                                                                              CH C N.sub.2 C.sub.4 H.sub.9                                                             Me                                                                              CO SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                  H                                         463                                                                              Me                                                                              CH C NC.sub.4 H.sub.8                                                                    Me                                                                              CO SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                  H                                         464                                                                              Me                                                                              CH C NEt.sub.2                                                                           Me                                                                              CO SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                  H                                         465                                                                              Me                                                                              CH C OH    Me                                                                              CO SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                  H                                         466                                                                              Me                                                                              CH C OMe   Me                                                                              CO SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                  H                                         467                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                  --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         468                                                                              --                                                                              -- N NC.sub.3 H.sub.6                                                                    --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         469                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                    --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         470                                                                              --                                                                              -- N NC.sub.5 H.sub.10                                                                   --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         471                                                                              --                                                                              -- N NC.sub.4 H.sub.8 S                                                                  --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         472                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                             --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         473                                                                              --                                                                              -- N NH.sub.2                                                                            --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         474                                                                              --                                                                              -- N NHMe  --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         475                                                                              --                                                                              -- N NHEt  --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         476                                                                              --                                                                              -- N NMe.sub.2                                                                           --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         477                                                                              --                                                                              -- N NEt.sub.2                                                                           --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         478                                                                              --                                                                              -- N OH    --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         479                                                                              --                                                                              -- N OMe   --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         480                                                                              --                                                                              -- N OEt   --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                         481                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                  --                                                                              CO --                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                         482                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                  --                                                                              CO --                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                         483                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                  --                                                                              CO --                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                H                                         484                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                  --                                                                              CO --                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                               H                                         485                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                  --                                                                              CO --                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                               H                                         486                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                             --                                                                              CO --                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                         487                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                    --                                                                              CO --                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                         488                                                                              --                                                                              -- N NEt.sub.2                                                                           --                                                                              CO --                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                         489                                                                              --                                                                              -- N OH    --                                                                              CO --                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                H                                         490                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                             --                                                                              CO --                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                H                                         __________________________________________________________________________

                                      TABLE 15                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A  Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                          R.sup.8                                                                         R.sup.12      R.sup.13                                  __________________________________________________________________________    491                                                                              --                                                                              -- N C.sub.4 H.sub.8                                                                    --                                                                              CO --                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         492                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         493                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         494                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         495                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         496                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         497                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         498                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         499                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         500                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         501                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         502                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         503                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         504                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         505                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         506                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         507                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         508                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         509                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         510                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         511                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         512                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         513                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         514                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         515                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         516                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         517                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         518                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         519                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         520                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         521                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         522                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         523                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         524                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         525                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         __________________________________________________________________________

                                      TABLE 16                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A  Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                          R.sup.8                                                                         R.sup.12      R.sup.13                                  __________________________________________________________________________    526                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         527                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         528                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         529                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         530                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         531                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         532                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         533                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                         534                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                         535                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                         536                                                                              --                                                                              -- N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                         537                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         538                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         539                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         540                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         541                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         542                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         543                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         544                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         545                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                         546                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                         547                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                         548                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                         549                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                         550                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                         551                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                         552                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                         553                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                         554                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                         555                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                         556                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                         557                                                                              --                                                                              -- N N.sub.2 C.sub.4 H.sub.9                                                            --                                                                              CO --                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                         558                                                                              --                                                                              -- N NC.sub.4 H.sub.8                                                                   --                                                                              CO --                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                         559                                                                              --                                                                              -- N NEt.sub.2                                                                          --                                                                              CO --                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                         560                                                                              --                                                                              -- N OH   --                                                                              CO --                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                         __________________________________________________________________________

                                      TABLE 17                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                          A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                          R.sup.8                                                                         R.sup.12     R.sup.13                                   __________________________________________________________________________    561                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                CF.sub.3                                   562                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                Ph                                         563                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                CH.sub.2 Ph                                564                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                (CH.sub.2).sub.2 Ph                        565                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                NHCOCH.sub.2 Ph                            566                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                NHCO(CH.sub.2).sub.2 Ph                    567                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                NHCOCHPh.sub.2                             568                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                CH.sub.3                                   569                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                CF.sub.3                                   570                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                Ph                                         571                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                CH.sub.2 Ph                                572                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                (CH.sub.2).sub.2 Ph                        573                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                NHCOCH.sub.2 Ph                            574                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                NHCO(CH.sub.2).sub.2 Ph                    575                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                NHCOCHPh.sub.2                             576                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                CH.sub.3                                   577                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                CF.sub.3                                   578                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                Ph                                         579                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                CH.sub.2 Ph                                580                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                (CH.sub.2).sub.2 Ph                        581                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                NHCOCH.sub.2 Ph                            582                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                NHCO(CH.sub.2).sub.2 Ph                    583                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                NHCOCHPh.sub.2                             584                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                CH.sub.3                                   585                                                                              nBu                                                                              N C NC.sub.4 H.sub.8 O                                                                 H CO CO                                                                              NHCH.sub.2 PhPh-2-CN.sub.4 H                                                               H                                          586                                                                              nBu                                                                              N C NEt.sub.2                                                                          H CO CO                                                                              NHCH.sub.2 PhPh-2-CN.sub.4 H                                                               H                                          587                                                                              nBu                                                                              N C NC.sub.4 H.sub.8 O                                                                 H CO CO                                                                              OCH.sub.2 PhPh-2-CN.sub.4 H                                                                H                                          588                                                                              nBu                                                                              N C NEt.sub.2                                                                          H CO CO                                                                              OCH.sub.2 Ph-4-COOH                                                                        H                                          589                                                                              nPen                                                                             N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              OCH.sub.2 Ph-4-COOH                                                                        H                                          590                                                                              nPen                                                                             N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              NHCH.sub.2 PhPh-2-CN.sub.4 H                                                               H                                          591                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 PhPh-2-CN.sub.4 H                                                        H                                          592                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 H CO CO                                                                              N(CO-nBu)CH.sub.2 PhPh-2-CN.sub.4 H                                                        H                                          593                                                                              nPen                                                                             N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              NHCH.sub.2 PhPh-2-CN.sub.4 H                                                               NHCOCHPh.sub.2                             594                                                                              nBu                                                                              N C NC.sub.4 H.sub.8 O                                                                 H CO CO                                                                              N(CH.sub.2 PhPh-2-CN.sub.4 H).sub.2                                                        H                                          595                                                                              nPen                                                                             N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              SO.sub.2                                                                         SB                                                                              NHCH.sub.2 PhPh-2-CN.sub.4 H                                                               H                                          __________________________________________________________________________

                                      TABLE 18                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                          A Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                          R.sup.8                                                                         R.sup.12     R.sup.13                                   __________________________________________________________________________    596                                                                              nPen                                                                             N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              SO.sub.2                                                                         SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       H                                          597                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              SO.sub.2                                                                         SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                          598                                                                              nPen                                                                             N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              SO.sub.2                                                                         SB                                                                              NHCH.sub.2 Ph-4-COOH                                                                       NHCOCHPh.sub.2                             599                                                                              nPen                                                                             N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              SO.sub.2                                                                         SB                                                                              NHCH.sub.2 PhPh-2-CN.sub.4 H                                                               NHCO(CH.sub.2).sub.2 Ph                    600                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOMe                                                               H                                          601                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-OMe                                                                 H                                          602                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH Ph-4-OH                                                                        H                                          603                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-NH.sub.2                                                            H                                          604                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-CN.sub.4 H                                                          H                                          605                                                                              Me N C NC.sub.4 H.sub.8 O                                                                 Me                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-SO.sub.3 H                                                          H                                          606                                                                              H  CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOMe                                                               H                                          607                                                                              H  CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-OMe                                                                 H                                          608                                                                              H  CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-OH                                                                  H                                          609                                                                              H  CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-NH.sub.2                                                            H                                          610                                                                              H  CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-CN.sub.4 H                                                          H                                          611                                                                              H  CH                                                                              C NC.sub.4 H.sub.8 O                                                                 H CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-SO.sub.3 H                                                          H                                          612                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOMe                                                               H                                          613                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-OMe                                                                 H                                          614                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-OH                                                                  H                                          615                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-NH.sub.2                                                            H                                          616                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-CN.sub.4 H                                                          H                                          617                                                                              -- --                                                                              CH                                                                              NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-SO.sub.3 H                                                          H                                          618                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOMe                                                               H                                          619                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-OMe                                                                 H                                          620                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-OH                                                                  H                                          621                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-NH.sub.2                                                            H                                          622                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-CN.sub.4 H                                                          H                                          623                                                                              -- --                                                                              N NC.sub.4 H.sub.8 O                                                                 --                                                                              CO --                                                                              N(CO-nBu)CH.sub.2 Ph-4-SO.sub.3 H                                                          H                                          624                                                                              Et N C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                          625                                                                              Et N C NC.sub.3 H.sub.6                                                                   Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                          626                                                                              Et N C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                          627                                                                              Et N C NC.sub.5 H.sub.10                                                                  Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                          628                                                                              Et N C NC.sub.4 H.sub.8 S                                                                 Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                          629                                                                              Et N C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                          630                                                                              Et N C NH.sub.2                                                                           Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                H                                          __________________________________________________________________________

                                      TABLE 19                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A  Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                          R.sup.8                                                                         R.sup.12      R.sup.13                                  __________________________________________________________________________    631                                                                              Et                                                                              N  C NHMe Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         632                                                                              Et                                                                              N  C NHEt Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         633                                                                              Et                                                                              N  C NMe.sub.2                                                                          Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         634                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         635                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         636                                                                              Et                                                                              N  C OMe  Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         637                                                                              Et                                                                              N  C OEt  Et                                                                              CO SB                                                                              N(CO-nBu)CH.sub.2 Ph-4-COOH                                                                 H                                         638                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                         639                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         640                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         641                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         642                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         643                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                         644                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                         645                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                         646                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CO--Me)CH.sub.2 Ph-4-COOH                                                                 H                                         647                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         648                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         649                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         650                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CO--Et)CH.sub.2 Ph-4-COOH                                                                 H                                         651                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         652                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         653                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         654                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CO-nPr)CH.sub.2 Ph-4-COOH                                                                 H                                         655                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         656                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         657                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         658                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CO-nPen)CH.sub.2 Ph-4-COOH                                                                H                                         659                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         660                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         661                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         662                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CO-nHex)CH.sub.2 Ph-4-COOH                                                                H                                         663                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         664                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         665                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         __________________________________________________________________________

                                      TABLE 20                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                         A  Z R.sup.2                                                                            R.sup.4                                                                         R.sup.7                                                                          R.sup.8                                                                         R.sup.12      R.sup.13                                  __________________________________________________________________________    666                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         667                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         668                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         669                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         670                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         671                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CONH--Me)CH.sub.2 Ph-4-COOH                                                               H                                         672                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         673                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         674                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         675                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CONH--Et)CH.sub.2 Ph-4-COOH                                                               H                                         676                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         677                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         678                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         679                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CONH-nPr)CH.sub.2 Ph-4-COOH                                                               H                                         680                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         681                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         682                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         683                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CONH-nBu)CH.sub.2 Ph-4-COOH                                                               H                                         684                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         685                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         686                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         687                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(CONH-nPen)CH.sub.2 Ph-4-COOH                                                              H                                         688                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         689                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         690                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(nPr)CH.sub.2 Ph-4-COOH                                                                    H                                         691                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(nBu)CH.sub.2 Ph-4-COOH                                                                    H                                         692                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(nPen)CH.sub.2 Ph-4-COOH                                                                   H                                         693                                                                              Et                                                                              N  C NC.sub.4 H.sub.8 O                                                                 Et                                                                              CO SB                                                                              N(nHex)CH.sub.2 Ph-4-COOH                                                                   H                                         694                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         695                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         696                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         697                                                                              Et                                                                              N  C OH   Et                                                                              CO SB                                                                              N(Me)CH.sub.2 Ph-4-COOH                                                                     H                                         698                                                                              Et                                                                              N  C N.sub.2 C.sub.4 H.sub.9                                                            Et                                                                              CO SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         699                                                                              Et                                                                              N  C NC.sub.4 H.sub.8                                                                   Et                                                                              CO SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         700                                                                              Et                                                                              N  C NEt.sub.2                                                                          Et                                                                              CO SB                                                                              N(Et)CH.sub.2 Ph-4-COOH                                                                     H                                         __________________________________________________________________________

                                      TABLE 21                                    __________________________________________________________________________    No.                                                                              R.sup.1                                                                          A Z  R.sup.2                                                                            R.sup.4                                                                          R.sup.7                                                                         R.sup.8                                                                          R.sup.12    R.sup.13                                  __________________________________________________________________________    701                                                                              Et N C  OH   Et CO                                                                              SB N(Et)CH.sub.2 Ph-4-COOH                                                                   H                                         702                                                                              Et N C  N.sub.2 C.sub.4 H.sub.9                                                            Et CO                                                                              SB N(nPr)CH.sub.2 Ph-4-COOH                                                                  H                                         703                                                                              Et N C  NC.sub.4 H.sub.8                                                                   Et CO                                                                              SB N(nPr)CH.sub.2 Ph-4-COOH                                                                  H                                         704                                                                              Et N C  NEt.sub.2                                                                          Et CO                                                                              SB N(nPr)CH.sub.2 Ph-4-COOH                                                                  H                                         705                                                                              Et N C  OH   Et CO                                                                              SB N(nPr)CH.sub.2 Ph-4-COOH                                                                  H                                         706                                                                              Et N C  N.sub.2 C.sub.4 H.sub.9                                                            Et CO                                                                              SB N(nBu)CH.sub.2 Ph-4-COOH                                                                  H                                         707                                                                              Et N C  NC.sub.4 H.sub.8                                                                   Et CO                                                                              SB N(nBu)CH.sub.2 Ph-4-COOH                                                                  H                                         708                                                                              Et N C  NEt.sub.2                                                                          Et CO                                                                              SB N(nBu)CH.sub.2 Ph-4-COOH                                                                  H                                         709                                                                              Et N C  OH   Et CO                                                                              SB N(nBu)CH.sub.2 Ph-4-COOH                                                                  H                                         710                                                                              Et N C  N.sub.2 C.sub.4 H.sub.9                                                            Et CO                                                                              SB N(nPen)CH.sub.2 Ph-4-COOH                                                                 H                                         711                                                                              Et N C  NC.sub.4 H.sub.8                                                                   Et CO                                                                              SB N(nPen)CH Ph-4-COOH                                                                       H                                         712                                                                              Et N C  NEt.sub.2                                                                          Et CO                                                                              SB N(nPen)CH.sub.2 Ph-4-COOH                                                                 H                                         713                                                                              Et N C  OH   Et CO                                                                              SB N(nPen)CH.sub.2 Ph-4-COOH                                                                 H                                         714                                                                              Et N C  N.sub.2 C.sub.4 H.sub.9                                                            Et CO                                                                              SB N(nHex)CH.sub.2 Ph-4-COOH                                                                 H                                         715                                                                              Et N C  NC.sub.4 H.sub.8                                                                   Et CO                                                                              SB N(nHex)CH.sub.2 Ph-4-COOH                                                                 H                                         716                                                                              Et N C  NEt.sub.2                                                                          Et CO                                                                              SB N(nHex)CH.sub.2 Ph-4-COOH                                                                 H                                         717                                                                              Et N C  OH   Et CO                                                                              SB N(nHex)CH.sub.2 Ph-4-COOH                                                                 H                                         __________________________________________________________________________

The compounds of the present invention may be prepared by a processknown per se. The typical schemes which may be used to prepare thecompounds of the present invention will be illustrated hereinafter. Inthe following schemes, (H) means a hydrogen atom which may be optionallysubstituted for the illustrated group. ##STR3##

Step 1!-(a)

The compound of the formula (11) wherein R¹ and R⁸ have the samemeanings as above! is dissolved in an organic solvent, such astetrahydrofuran, acetone, dichloromethane, pyridine, triethylamine, orN,N-dimethylformamide. Further, the compound capable of converting the--COOH group to the --COR² group wherein R² is three- to seven-memberedsaturated cycloaliphatic amino group which may be interrupted by one ormore nitrogen, oxygen or sulfur atoms, --NHR²³, --N(R²⁴)₂, or --NH₂group! is also dissolved in an organic solvent, such as those mentionedabove. Then, the latter solution is added to the former solution, andthe reaction is performed in the presence of an appropriate condensationagent at 0° to 100° C. for 3 to 72 hours to obtain the compound of theformula (12) wherein R¹, R², and R⁸ have the same meanings as above!.The compound capable of converting the --COOH group to the --COR² groupis, for example, morpholine when R² is morpholino group. When R² is thegroup other than morpholino group, such a compound can be appropriatelyselected in view of the desired R² group by those skilled in the art.

Step 1!-(b)

The compound of the formula (12) is dissolved in a solvent, such asacetone, dichloromethane, tetrahydrofuran, pyridine, alcohol, ethylacetate, or N,N-dimethylformamide. Alkyl iodide having 1 to 6 carbonatoms and silver (I) oxide are added thereto. The reaction is performedwith stirring for 3 to 72 hours to obtain the compound of the formula(13) wherein R⁴ is alkyl of 1 to 6 carbon atoms, and R¹, R² and R⁸ havethe same meanings as above!.

Step 1!-(c), (c')

The compound of the formula (12) or (13) is dissolved in a solvent, suchas alcohol or ethyl acetate. After an appropriate reducing agent, suchas tin (II) chloride dihydrate, or 10% palladium/carbon and hydrazinemonohydrate, is added, the reaction is performed at 20° to 100° C. toobtain the compound of the formula (14) wherein R¹, R², R⁴ and R⁸ havethe same meanings as above!.

Step 1!-(d)

The compound of the formula (14) is dissolved in a solvent, such astoluene, acetonitrile, diisopropylethylamine, dichloromethane, ethylacetate, alcohol, or benzene, and then reacted with the compound of theformula

R⁶ X

wherein X is a halogen atom, --OH or --COOH; R⁶ is --C(═O)(CH₂)_(a) C₆H₅, --C(═O)R⁴¹, --C(═O)CH(C₆ H₅)₂, or alkyl of 1 to 6 carbon atoms; a is0 or an integer of 1 to 6; and R⁴¹ is alkyl 1 to 6 carbon atoms, toobtain the compound of the formula (15).

Step 1!-(e), (e')

The compound of the formula (14) or (15) is dissolved in a solvent, suchas chloroform, benzene, or pyridine. After the compound of the formula

R⁵ Y

wherein R⁵ has the same meaning as above, and Y is a leaving group, suchas a halogen atom, and diisopropylethylamine are added, the whole isheated under reflux for 1 hour to 5 days to obtain the compound of theformula (16). If necessary, one or more protective groups may beremoved.

Step 1!-(f)

The compound of the formula (16) is dissolved in a solvent, such asN,N-dimethylformamide, tetrahydrofuran, chloroform, benzene, orpyridine. After alkyl halide of 1 to 6 carbon atoms, alkylcarbonylhalide having 1 to 6 carbon atoms in the alkyl moiety, alkylcarboxylicacid having 1 to 7 carbon atoms, or alkyl isocyanate of 1 to 7 carbonatoms is added, the reaction is performed to obtain the compound of theformula (17) wherein R¹, R², R⁴, R⁵ and R⁶ have the same meanings asabove; R⁹ is --COR⁴², alkyl of 1 to 6 carbon --C(═O)NH₂, or --C(═O)NHR⁴³; R⁴² is alkyl of 1 to 6 carbon atoms; and R⁴³ is alkyl of 1 to 6 carbonatoms!. If necessary, one or more protective groups may be removed.##STR4##

Step 2!-(a)

The sulfonyl chloride compound of the formula (21) us dissolved in anorganic solvent, such as dichloromethane, pyridine, or triethylamine.Further, the compound capable of converting the --SO₂ Cl group to the--SO₂ R² group wherein R² is three- to seven-membered saturatedcycloaliphatic amino group which may be interrupted by one or morenitrogen, oxygen or sulfur atoms, --NHR²³, --N(R²⁴)₂, or --NH₂ group! isalso dissolved in an organic solvent, such as those mentioned above.Then, the latter solution is added to the former solution, and thereaction is performed at -78° to 25° C. for 3 to 10 hours to obtain thecompound of the formula (22) wherein R² has the same meaning as above!.The compound capable of converting the --SO₂ Cl group to the --SO₂ R²group is, for example, morpholine when R² is morpholino group. When R²is the group other than morpholino group, such a compound can beappropriately selected in view of the desired R² group b those skilledin the art.

Step 2!-(b)

The compound of the formula (22) is dissolved in a solvent, such asacetone, dichloromethane, tetrahydrofuran, pyridine, alcohol, or water.The compound of the formula R¹ NH₂ wherein R¹ has the same meaning asabove! is added after dissolved in dichloromethane, tetrahydrofuran,pyridine, or alcohol if necessary, and the reaction is performed at -78°to 100° C. to obtain the compound of the formula (23).

Step 2!-(c)

The compound of the formula (23) is dissolved in a solvent, such asN,N-dimethylformamide. Alkyl iodide having 1 to 6 carbon atoms andsilver (I) oxide are added thereto. The reaction is performed for 3 to72 hours to obtain the compound of the formula (24) wherein R⁴ is alkylof 1 to 6 carbon atoms, and R¹ and R² have the same meanings as above!.

Step 2!-(d), (d')

The compound of the formula (23) or (24) is dissolved in a solvent, suchas ethyl acetate or alcohol. After an appropriate reducing agent, suchas tin (II) chloride dihydrate, or 10% palladium/carbon and hydrazinemonohydrate, is added, the reaction is performed at 20° to 100° C. toobtain the compound of the formula (25) wherein R¹, R² and R⁴ have thesame meanings as above!.

Step 2!-(e), (f), (f')

The compound of the formula (25) is dissolved in a solvent, such astoluene, dichloromethane, ethyl acetate, tetrahydrofuran, acetonitrile,alcohol, benzene, or N,N-dimethylformamide, and then reacted with thecompound having a desired substituent, and if necessary, one or moreprotective groups are removed to obtain the compound of the formula (26)or (27) wherein R¹, R², R⁴, R⁵ and R⁶ have the same meanings as above!.##STR5##

Step 3!-(a)

The compound of the formula (31) wherein R¹³ has the same meaning asabove! is dissolved in a solvent, such as chloroform, tetrahydrofuran,acetone, pyridine, alcohol, or N,N-dimethylformamide, and reacted withthe compound capable of converting the --COOH group to the --COR² groupwherein R² has the same meaning as above! and an appropriatecondensation agent to obtain the compound of the formula (32). Thecompound capable of converting the --COOH group to the --COR² group is,for example, morpholine when R² is morpholino group. When R² is thegroup other than morpholino group, such a compound can be appropriatelyselected in view of the desired R² group by those skilled in the art.

Step 3!-(b)

The compound of the formula (32) is reacted with the compound of theformula R⁵ Y wherein R⁵ and Y have the same meanings as above! in thepresence of a base, such as sodium hydride in a solvent, such aschloroform, tetrahydrofuran, acetone, pyridine, or N,N-dimethylformamideto obtain the compound of the formula (33).

Step 3!-(c)

The compound of the formula (33) is dissolved in a solvent, such asalcohol or ethyl acetate, and treated with an appropriate reducingagent, such as hydrazine monohydrate and 10% palladium/carbon, or tin(II) chloride dihydrate, at 20° to 100° C. to obtain the compound of theformula (34).

Step 3!-(d)

The compound of the formula (34) is dissolved in a solvent, such aspyridine, and then reacted with the compound having a desiredsubstituent at -10° to 100° C. to obtain the compound of the formula(35). If the resulting compound has one or more protective groups, suchgroups may be removed, using an acid and/or base. ##STR6##

Step 4!-(a)

The compound of the formula (41) wherein R¹³ has the same meaning asabove! is dissolved in a solvent, such as chloroform, tetrahydrofuran,benzene, pyridine, or N,N-dimethylformamide, and reacted with thecompound capable of converting the --COOH group to the --COR² groupwherein R² has the same meaning as above! and an appropriatecondensation agent to obtain the compound of the formula (42). Thecompound capable of converting the --COOH group to the --COR² group is,for example, diethylamine when R² is diethylamino group. When R² is thegroup other than morpholino group, such a compound can be appropriatelyselected in view of the desired R² group by those skilled in the art.

Step 4!-(b)

The compound of the formula (42) is dissolved in a solvent, such aspyridine, and then reacted with the compound having a desiredsubstituent at -10° to 100° C. to obtain the compound of the formula(43).

Step 4!-(c)

The compound of the formula (43) is dissolved in a solvent, such asalcohol or ethyl acetate, and treated with an appropriate reducingagent, such as hydrazine monohydrate and 10% palladium/carbon, or tin(II) chloride dihydrate, at 20° to 100° C. to obtain the compound of theformula (44).

Step 4!-(d)

The compound of the formula (44) is dissolved in a solvent, such asdiisopropylethylamine, pyridine, or chloroform, and reacted with thecompound of the formula R⁵ Y wherein R⁵ and Y have the same meanings asabove! at 20° to 100° C. to obtain the compound of the formula (45).

Step 4!-(e)

The compound of the formula (45) is dissolved in a solvent, such asdiisopropylethylamine or pyridine, and then reacted with the compoundhaving a desired substituent at -10° to 100° C. to obtain the compoundof the formula (46). If necessary, one or more protective groups may beremoved by treating with an acid and/or base. ##STR7##

Step 5!-(a), (a')

The compound of the formula (51) wherein R¹, R⁴, R¹³, and A have thesame meanings as above, and R⁴⁴ is a hydrogen atom or alkyl of 1 to 6carbon atoms! is dissolved in a solvent, such as acetic anhydride,fuming nitric acid is added and then the reaction is performed at -10°to 30° C. for 1 to 10 hours, or mixed acid of sulfuric and nitric acidsis added to the compound of the formula (51) and the reaction isperformed in the absence of a solvent at -10° to 30° C. for 1 to 10hours, to obtain the compound of the formula (52) wherein R¹, R⁴, R¹³,R⁴⁴, and A have the same meanings as above !.

Step 5!-(b)

The compound of the formula (52) is dissolved in a solvent, such asmethanol, ethanol, tetrahydrofuran or dioxane. The solution is treatedwith an alkaline aqueous solution at 10° C. to temperature below theboiling point of the solvent, cooled, and then, deposited with acid toobtain the compound of the formula (53) wherein R¹, R⁴, R¹³, and A havethe same meanings as above!.

Step 5!-(c)

The compound of the formula (53) is dissolved in a solvent, such aschloroform, tetrahydrofuran, benzene, pyridine, orN,N-dimethylformamide, and reacted with the compound capable ofconverting the --COOH group to the --COR² group wherein R² has the samemeaning as above! and an appropriate condensation agent to obtain thecompound of the formula (54) wherein R¹, R², R⁴, R¹³, and A have thesame meanings as above!. The compound capable of converting the --COOHgroup to the --COR² group is, for example, morpholine when R² ismorpholino group. When R² is the group other than morpholino group, sucha compound can be appropriately selected in view of the desired R² groupby those skilled in the art.

Step 5!-(d)

The compound of the formula (54) is dissolved in a solvent, such asalcohol or ethyl acetate, and treated with an appropriate reducingagent, such as hydrazine monohydrate and 10% palladium/carbon, tin (II)chloride dihydrate, or sodium hydrosulfite, at 20° to 100° C. to obtainthe compound of the formula (55).

Step 5!-(e)

The compound of the formula (55) is dissolved in a solvent, such aspyridine or N,N-dimethylformamide, and then reacted with the compoundhaving a desired substituent at -10° to 100° C. to obtain the compoundof the formula (56) wherein R¹, R², R⁴, R¹³, and A have the samemeanings as above, R⁴⁵ is a hydrogen atom, alkyl of 1 to 6 carbon atoms,haloalkyl of 1 to 6 carbon atoms, or NHR²¹, and R²¹ has the same meaningas above!.

Step 5!-(f)

The compound of the formula (56) is dissolved in a solvent, such asdimethylsulfoxide or N,N-dimethylformamide, and is reacted with thecompound of the formula R⁵ Y wherein R⁵ and Y have the same meanings asabove! in the presence of a base, such as sodium hydride or potassiumhydroxide at -20° to 100° C. to obtain the compound of the formula (57)wherein R¹, R², R⁴, R⁵, R¹³, R⁴⁵, and A have the same meanings asabove!. If necessary, one or more protective groups may be removed bytreating with an acid-and/or base.

Step 5!-(g)

The compound of the formula (55) is dissolved in a solvent, such asacetic acid, and then reacted with the compound having a desiredsubstituent at 0° to 100° C. The resulting compound is reacted with anappropriate reducing agent, such as borane-diethylamine complex, at 0°to 100° C. to obtain the compound of the formula (57) wherein R¹, R²,R⁴, R⁵, R¹³, R⁴⁵, and A have the same meanings as above!. If necessary,one or more protective groups may be removed by treating with an acidand/or base. ##STR8##

Step 6!-(a)

The compound of the formula (61) wherein R¹³ and R⁴⁴ have the samemeanings as above! is dissolved in a solvent, such as pyridine orN,N-dimethylformamide, and then reacted with the compound having adesired substituent at -10° to 100° C. to obtain the compound of theformula (62) wherein R¹, R¹³, and R⁴⁴ have the same meanings as above!.

Step 6!-(b)

The compound of the formula (62) is dissolved in a solvent, such asmethanol, ethanol, tetrahydrofuran or dioxane. The solution is treatedwith an alkaline aqueous solution at 10° C. to temperature below theboiling point of the solvent, cooled, and then, deposited with acid toobtain the compound of the formula (63) wherein R¹ and R¹³ have the samemeanings as above!.

Step 6!-(c)

The compound of the formula (63) is dissolved in a solvent, such aschloroform, tetrahydrofuran, benzene, pyridine, orN,N-dimethylformamide, and reacted with the compound capable ofconverting the --COOH group to the --COR² group wherein R² has the samemeaning as above! and an appropriate condensation agent to obtain thecompound of the formula (64) wherein R¹, R², and R¹³ have the samemeanings as above!. The compound capable of converting the --COOH groupto the --COR² group is, for example, morpholine when R² is morpholinogroup. When R² is the group other than morpholino group, such a compoundcan be appropriately selected in view of the desired R² group by thoseskilled in the art.

Step 6!-(d)

The compound of the formula (64) is dissolved in a solvent, such asdimethylsulfoxide or N,N-dimethylformamide, and is reacted with thecompound of the formula R⁵ Y wherein R⁵ and Y have the same meanings asabove! in the presence of a base, such as sodium hydride or potassiumhydroxide at -20° to 100° C. to obtain the compound of the formula (65)wherein R¹, R², R⁵, and R¹³ have the same meanings as above!. Ifnecessary, one or more protective groups may be removed by treating withan acid and/or base. ##STR9##

Step 7!-(a)

The compound of the formula (55) wherein R¹, R², R¹³, and A have thesame meanings as above! obtained in the above step 5!-(d), and ifnecessary an acid catalyst, such as tosyl anhydrous p-toluenesulfonicacid, are dissolved in a solvent, such as ethanol or benzene. After 5 to10% palladium/carbon is suspended, the compound of the formula R⁵¹ CHOwherein R⁵¹ is alkyl of 1 to 5 carbon atoms! is reacted therewith underhydrogen gas atmosphere at -20° to 100° C. to obtain the compound of theformula (71) wherein R¹, R², R⁴, R¹³, and A have the same meanings asabove, and R⁵⁰ is alkyl of 1 to 6 carbon atoms!.

Step 7!-(b)

The compound of the formula (71) wherein R¹, R², R⁴, R¹³, R⁵⁰, and Ahave the same meanings as above! is dissolved in a solvent, such asbenzene, toluene or chloroform. After the compound of the formula R⁵ Ywherein R⁵ and Y have the same meanings as above! and a base, such asdiisopropylethylamine, are added, the whole is heated under reflux for 1hour to 7 days to obtain the compound of the formula (72) wherein R¹,R², R⁴, R¹³, R⁵⁰, and A have the same meanings as above!. If necessary,one or more protective groups may be removed by treating with an acidand/or base. ##STR10##

Step 8!-(a)

As in the above step 1!-(a), the compound of the formula (81) is reactedwith the compound capable of converting the --COOH group to the --COR²group wherein R² has the same meaning as above! and an appropriatecondensation agent to obtain the compound of the formula (82) wherein R²has the same meaning as above!. The compound capable of converting the--COOH group to the --COR² group is, for example, morpholine, when R² ismorpholino group. When R² is the group other than morpholino group, sucha compound can be appropriately selected in view of the desired R² groupby those skilled in the art.

Step 8!-(b)

As in the above step 2!-(b), the compound of the formula (82) wherein R²has the same meaning as above! is reacted with the compound of theformula R¹ NH₂ wherein R¹ has the same meaning as above! to obtain thecompound of the formula (83) wherein R¹ and R² have the same meanings asabove!.

Step 8!-(c)

As in the above step 2!-(c), the compound of the formula (83) wherein R¹and R² have the same meanings as above! is reacted with alkyl iodide of1 to 6 carbon atoms or the like and silver (I) oxide to obtain thecompound of the formula (84) wherein R⁴ is alkyl of 1 to 6 carbon atoms,and R¹ and R² have the same meanings as above!.

Step 8!-(d)

As in the above step 2!-(d), the compound of the formula (84) whereinR¹, R² and R⁴ have the same meanings as above! is treated with anappropriate reducing agent to obtain the compound of the formula (85)wherein R¹, R² and R⁴ have the same meanings as above!.

Step 8!-(e)

The compound of the formula (85) wherein R¹, R² and R⁴ have the samemeanings as above! is dissolved in a non-polar solvent, such as benzene,or toluene. After a base, such as diisopropylethylamine, is added, thecompound of the formula R⁵ Y wherein R⁵ and Y have the same meanings asabove! is reacted at 20° to 100° C. to obtain the compound of theformula (86) wherein R¹, R², R⁴, and R⁵ have the same meanings asabove!. If necessary, one or more protective groups may be removed bytreating with an acid and/or base. ##STR11##

Step 9!-(a)

Phosphorus oxychloride or phosphorus oxybromide is added to the compoundof the formula (91) wherein R² has the same meaning as above!, and thereaction is performed 0° to 150° C. for 1 to 24 hours to obtain thecompound of the formula (92) wherein R² has the same meaning as above!.

Step 9!-(b)

Ammonia water is added to the compound of the formula (92) wherein R²has the same meaning as above!, and the reaction is performed 20° to200° C. for 3 to 72 hours to obtain the compound of the formula (93)wherein R² has the same meaning as above!.

Step 9!-(c)

The compound of the formula (93) wherein R² has the same meaning asabove! is dissolved in a solvent, such as pyridine orN,N-dimethylformamide, after protected if necessary, and reacted withthe compound having a desired substituent at -10° to 100° C. to obtainthe compound of the formula (94) wherein R² and R⁴⁵ have the samemeanings as above !.

Step 9!-(d)

After one or more protect groups are removed by alkaline treatment ifnecessary, and reaction with the compound having a desired substituentand an appropriate condensation agent is performed if necessary, thecompound of the formula (94) wherein R² and R⁴⁵ have the same meaningsas above! is dissolved in a solvent, such as dimethylsulfoxide orN,N-dimethylformamide, and reacted with the compound of the formula R⁵ Ywherein R⁵ and Y have the same meanings as above! in the presence of abase, such as sodium hydride or potassium hydroxide, at -20° to 100° C.to obtain the compound of the formula (95) wherein R², R⁵, and R⁴⁵ havethe same meanings as above!. If necessary, one or more protective groupsmay be removed by treating with an acid and/or base. ##STR12##

Step 10!-(a)

The compound of the formula (102) wherein R² has the same meaning asabove! is obtained from the starting compound of the formula (101) as inthe above step 1!-(a).

Step 10!-(b)

The compound of the formula (102) wherein R² has the same meaning asabove! is dissolved in the compound of the formula R⁴ NH₂ wherein R⁴ isalkyl of 1 to 6 carbon atoms!, and the solution is heated at 50° to 150°C. to obtain the compound of the formula (103) wherein R² and R⁴ havethe same meanings as above!.

Step 10!-(c)

The compound of the formula (103) wherein R² and R⁴ have the samemeanings as above! is dissolved in a non-polar solvent, such as benzeneor toluene. After a base, such as diisopropylethylamine, is added, thecompound of the formula R⁵ Y wherein R⁵ and Y have the same meanings asabove! is reacted at 20° to 150° C. to obtain the compound of theformula (104) wherein R², R⁴ and R⁵ have the same meanings as above!. Ifnecessary, one or more protective groups may be removed by treating withan acid and/or base. ##STR13##

Step 11!-(a)

The compound of the formula (112) wherein R² has the same meaning asabove! is obtained from the starting compound, sulfonylchloride of theformula (111) as in the above step 2!-(a).

Step 11!-(b)

The compound of the formula (112) wherein R² has the same meaning asabove! is dissolved in a solvent, such as cyclic ether (such astetrahydrofuran or dioxane) or water. After a secondary amine of theformula NHR¹ R⁴ wherein R¹ and R⁴ have the same meanings as above! isadded, the reaction is performed at 0° to 120° C. to obtain the compoundof the formula (113) wherein R¹, R² and R⁴ have the same meanings asabove!.

Step 11!-(c)

The compound of the formula (113) wherein R¹, R² and R⁴ have the samemeanings as above! is dissolved in lower alcohol. After an appropriatereducing agent, such as sodium hydrosulfite, or 10% palladium/carbon andhydrazine monohydrate, is added, the reaction is performed at -10° to100° C. to obtain the compound of the formula (114) wherein R¹, R² andR⁴ have the same meanings as above!.

Step 11!-(d)

As in the above step 5!-(e), the compound of the formula (114) whereinR¹, R² and R⁴ have the same meanings as above! is reacted with thecompound having a desired substituent to obtain the compound of theformula (115) wherein R¹, R², R⁴ and R⁴⁵ have the same meanings asabove!.

Step 11!-(c)

As in the above step 5!-(f), the compound of the formula (115) whereinR¹, R², R⁴ and R⁴⁵ have the same meanings as above! is reacted with thecompound of the formula R⁵ Y wherein R⁵ and Y have the same meanings asabove! in the presence of a base, such as sodium hydride or potassiumhydroxide, to obtain the compound of the formula (116) wherein R¹, R²,R⁴, R⁵ and R⁴⁵ have the same meanings as above!. If necessary, one ormore protective groups may be removed by treating with an acid and/orbase. ##STR14##

Step 12!-(a)

The compound of the formula (55) wherein R¹, R², R⁴, R¹³, and A have thesame meanings as above! obtained in the above step 5!-(d) is dissolvedin a solvent, such as glacial acetic acid or benzene, and reacted withthe compound of the formula R⁵³ CHO wherein R⁵³ is --C₆ H₄ COOR⁵⁴, --C₆H₄ OR⁵⁴, --C₆ H₄ N(R⁵⁴)₂, or --C₆ H₄ -azole, and R⁵⁴ is hydrogen atom oralkyl of 1 to 6 carbon atoms! and if necessary an acid catalyst, such asanhydrous p-toluenesulfonic acid, at -20° to 100° C. After adding areducing agent, such as boranediethylamine complex, the reaction isfurther performed at -20° to 100° C. to obtain the compound of theformula (121) wherein R¹, R², R⁴, R⁵, R¹³, and A have the same meaningsas above!.

Step 12!-(b)

The compound of the formula (121) wherein R¹, R², R⁴, R⁵, R¹³, and Ahave the same meanings as above! is dissolved in a solvent, such asbenzene, toluene, chloroform or pyridine, and reacted with theisocyanate compound of the formula R⁵² N═C═O wherein R⁵² is alkyl of 1to 5 carbon atoms! at -20° to 150° C. to obtain the compound of theformula (122) wherein R¹, R², R⁴, R⁵, R¹³, R⁵², and A have the samemeanings as above!. If necessary, one or more protective groups may beremoved by treating with an acid and/or base. ##STR15##

Step 13!-(a)

The compound of the formula (131) wherein R¹³ has the same meaning asabove! is dissolved in a solvent, such as tetrahydrofuran orN,N-dimethylformamide, and reacted with the compound capable ofconverting the --COOH group to the --COR² group wherein R² has the samemeaning as above! and an appropriate condensation agent to obtain thecompound of the formula (132) wherein R² and R¹³ have the same meaningsas above!. The compound capable of converting the --COOH group to the--COR² group is, for example, morpholine, when R² is morpholino group.When R² is the group other than morpholino group, such a compound can beappropriately selected in view of the desired R² group by those skilledin the art.

Step 13!-(b)

The compound of the formula (132) wherein R² and R¹³ have the samemeanings as above! is dissolved in a solvent, such as alcohol or ethylacetate. After an appropriate reducing agent, such as hydrazinemonohydrate and 10% palladium/carbon, tin (II) chloride dihydrate, orsodium hydrosulfite, the reaction is performed at 20° to 100° C. toobtain the compound of the formula (133) wherein R² and R¹³ have thesame meanings as above!.

Step 13!-(c)

The compound of the formula (133) wherein R² and R¹³ have the samemeanings as above!, and if necessary an acid catalyst, such as anhydrousp-toluenesulfonic acid, are dissolved in a solvent, such as ethanol orbenzene. After 5 to 10% palladium/carbon is suspended, the compound ofthe formula R⁵⁶ CHO wherein R⁵⁶ is alkyl of 1 to 5 carbon atoms! isreacted therewith under hydrogen gas atmosphere at -20° to 100° C. toobtain the compound of the formula (134) wherein R² and R¹³ have thesame meanings as above, and R⁵⁵ is alkyl of 1 to 6 carbon atoms!.

Step 13!-(d)

The compound of the formula (134) wherein R², R¹³ and R⁵⁵ have the samemeanings as above! is dissolved in a solvent, such as benzene, tolueneor chloroform. After the compound of the formula R⁵ Y wherein R⁵ and Yhave the same meanings as above! and a base, such asdiisopropylethylamine, are added, the whole is heated under reflux for 1hour to 7 days to obtain the compound of the formula (135) wherein R²,R⁵, R¹³ and R⁵⁵ have the same meanings as above!. If necessary, one ormore protective groups may be removed by treating with an acid and/orbase.

The ester compound of the formula (I) can be hydrolyzed in an organicsolvent, such as methanol, ethanol, butanol or tetrahydrofuran in thepresence of alkaline aqueous solution at 0° to 100° C. for 1 to 72 hoursand deposited with acid, and then converted to the free compound of theformula (I).

Further, the salt, particularly the pharmaceutically acceptable salt, ofthe compound of the formula (I) can be prepared by utilizing thecompound of the formula (I) and an equivalent amount of an alkali or anacid, evaporating the solvent or concentrating the solution, and dryingand purifying the residue.

The benzene derivative of the formula (I) according to the presentinvention or the pharmaceutically acceptable salt thereof issufficiently effective in improvement of the renal dysfunction withoutany function to blood pressure. Therefore, the present invention relatesto a pharmaceutical composition, particularly an anti-kidney diseaseagent, containing the benzene derivative of the formula (I) or thepharmaceutically acceptable salt thereof as an active ingredient.

The compound of the formula (I) is effective as an agent for treating akidney disease, such as nephritis, nephropathy, renal failure, nephroticsyndrome, asymptomatic proteinuria, hematuria, diabetic nephropathy,kidney disease induced by medicine, urinary tract infectious disease, orprostatitis. The compound of the formula (I) according to the presentinvention may be administered orally or parenterally (such aspercutaneously, intravenously or intraperitoneally).

The compound of the formula (I) according to the present invention wasorally administered to mice at the dose of 500 mg/kg, but no death wasobserved during one week.

The compound of the formula (I) may be formulated by adding one or morepharmaceutically acceptable additives, to powder, tablet, granule,capsule, suppository, injection, or oral solution. As the additives,there may be mentioned, for example, magnesium stearate, talc, lactose,dextrin, starches, methylcellulose, fatty acid glycerides, water,propyleneglycol, macrogols, alcohols, crystalline celluloses,hydroxypropylcellulose, low substituted hydroxypropylcellulose,carmelloses, povidone, polyvinylalcohol, or calcium stearate. Further,coloring agent, stabilizer, antioxidant, preservative, pH adjustingagent, isotonicity, solubilizing agent and/or soothing agent may becontained, if necessary. The granule, tablet, or capsule may be coatedwith a coating base, such as hydroxypropylmethyl cellulose orhydroxypropylmethyl cellulose phthalate.

The compound of the formula (I) may be contained at an amount of 0.1 to500 mg, preferably 1 to 100 mg in a dose unit. The dose of the compoundof the formula (I) is 0.1 to 150 mg/kg body weight, preferably 1 to 100mg/kg body weight. The dose may be administered once a day, or dividedtwice or 3 times a day. The dose may be appropriately selected withrespect to symptom of the patient.

The inventors of the present invention analyzed the three-dimensionalstructure of angiotensin II in solution by means of a method asoriginally developed, and studied the properties of various compounds,taking into account the affinities to angiotensin II in solution. Moreparticularly, antagonism to angiotensin II receptor subtype 1 which isknown to participates in antihypertensive function, a function toimprove renal dysfunction in a renal dysfunction model animal, afunction against blood pressure or the like were investigated in detail.As a result, the inventors found the compound of the formula (I) or asalt thereof has desired properties which are completely different fromthose of conventionally known antihypertensive compounds.

As mentioned above, the compound of the formula (I) or a salt thereofexhibits antagonism to the angiotensin II receptor subtype 1 which isone-hundredth (1/100) to one-thousandth (1/1000) or less as large asthat of the conventionally known antagonist having a standard activityas an antihypertensive agent. The compound of the formula (I) or a saltthereof exhibits a function to improve renal dysfunction withoutsubstantial antagonism. In view of the conventional knowledge, it isgreatly surprising that there exist compounds having such properties. Itis still unclear how the compound of the formula (I) exhibits suchproperties. It is assumed that the properties are brought about from,for example, the specific antagonism to a angiotensin II receptor (i.e.,a new receptor other than the known subtypes 1 and 2) which participatesin renal interstitial cell growth causing exacerbation of renal failure,or accumulation of the compound to kidney, although the presentinvention is not limited to said assumption. Further, there is apossibility of a mechanism completely different from that of antagonismto angiotensin II receptor.

Even if the compound of the formula (I) according to the presentinvention or a salt thereof is classified in an angiotensin II receptorantagonist, it has the properties essentially different from those ofthe known angiotensin II receptor antagonists which have been developedas an antihypertensive agent, i.e., the antagonists having a strongantagonism to the receptor and a function to lower blood pressure. Ifthe compound of the formula (I) or a salt thereof is not classified inan angiotensin II receptor antagonist, it is apparently differenttherefrom. Accordingly, the compound of the formula (I) according to thepresent invention or a salt thereof is novel with respect to thechemical structure, functional effects, and medical utility.

As above, the compound of the formula (I) according to the presentinvention or a salt thereof is sufficiently effective to renaldysfunction without affecting blood pressure. Therefore, it is possibleto appropriately treat kidney diseases without any such problem as acuterenal failure with the drugs having such properties while controllingblood pressure at a desired level by means of a suitableantihypertensive drug if necessary.

EXAMPLES

The present invention now will be further illustrated by, but is by nomeans limited to, the following Examples.

Example 1 Preparation of 3-nitro-4-valeramidobenzoic acid morpholide (1!-(12)-1)

In tetrahydrofuran (800 ml), 3-nitro-4-valeramidobenzoic acid (1!-(11)-1) (20.0 g) was dissolved. Dicyclohexylcarbodiimide (17.1 g) and1-hydroxybenzotriazole (11.2 g) were added to the solution, and themixture was stirred at room temperature for 15 minutes. Morpholine (7.27g) was further added to the solution. The mixture was stirred for 16hours. After the insolubles were removed from the reaction solution, thesolution was concentrated and dried. The crude product was dissolved inchloroform, and the insolubles were removed, and the solution waspurified by silica gel column chromatography (Kieselgel 60=400 g,chloroform/methanol=30/1) to obtain the compound ( 1!-(12)-1) (22.95 g)as yellow needle crystals.

Melting point: 126.0°-126.5° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.97 (t,3H), 1.44 (sext, 2H), 1.75 (quint, 2H), 2.52 (t, 2H), 3.4-3.9 (br, 8H),7.69 (d, 1H), 8.34 (s, 1H), 8.95 (d, 1H), 10.42 (s, 1H)

Example 2 Preparation of 3-amino-4-valeramidobenzoic acid morpholide (1!-(14)-1)

The compound ( 1!-(12)-1) (8.00 g) prepared in Example 1 was dissolvedin ethanol (800 ml) and heated to 50° C. Hydrazine monohydrate (8.0 ml)and 10% Pd/C (0.8 g) were added to the reaction solution, and the wholewas stirred for 10 minutes. After the reaction solution was filteredthrough celite, the filtrate was concentrated and recrystallized fromchloroform/hexane to obtain the compound ( 1!-(14)-1) (6.97 g) ascolorless needle crystals.

Melting point: 203.0°-205.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.97 (t,3H), 1.43 (sext, 2H), 1.73 (quint, 2H), 2.43 (t, 2H), 3.4-3.9 (br, 8H),3.88 (s, 2H), 6.65 (d, 1H), 6.71 (s, 1H), 7.06 (d, 1H), 7.92 (s, 1H)

Example 3 Preparation of 3-(4-methoxycarbonylphenyl)methylamino!-4-valeramidobenzoic acidmorpholide ( 1!-(16)-1')

The compound ( 1!-(14)-1) (6.10 g) prepared in Example 2 was suspendedin benzene (600 ml), and methyl 4-bromomethylbenzoate (4.81 g) anddiisopropylethylamine (25.8 g) were added to the suspension. Then, thereaction mixture was refluxed for 2 days. The reaction mixture wasconcentrated and the solvent was evaporated. The residue was purified bysilica gel column chromatography (Kieselgel 60=260 g, ethylacetate/hexane=5/1) to obtain the compound ( 1!-(16)-1') (7.71 g) aswhite foam.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.94 (t, 3H), 1.39 (sext, 2H), 1.71 (quint,2H), 2.44 (t, 2H), 3.0-3.9 (br, 8H), 3.91 (s, 3H), 4.37 (s, 2H), 4.76(s, 1H), 6.45 (s, 1H), 6.62 (d, 1H), 7.01 (d, 1H), 7.41 (d, 2H), 7.95(s, 1H), 7.99 (d, 1H)

Example 4 Preparation of 3-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methylamino-4-valeramidobenzoic acid morpholide ( 1!-(16)-585') and 3-di-2'-(1-triphenylmethyltetrazol-5-yl!biphenyl-4-yl!methylamino-4-valeramidobenzoicacid morpholide ( 1!-(16)-594')

The compound ( 1!-(14)-1) (13.0 g) prepared in Example 2 was dissolvedin chloroform (1000 ml), and N-(triphenylmethyl)-5-4'-(bromomethyl)biphenyl-2-yl!tetrazole (26.1 g) anddiisopropylethylamine (55.0 g) were added. Then, the reaction mixturewas refluxed for 4 days. The reaction mixture was concentrated. Theresidue was purified by silica gel column chromatography (Kieselgel60=150 g, ethyl acetate/hexane=3/1) to obtain the compound (1!-(16)-585') (19.6 g) and the compound ( 1!-(16)-594') (10.4 g) aswhite foam, respectively.

Compound ( 1!-(16)-585')

¹ H-NMR (500 MHz, CDCl₃) δ: 0.90 (t, 3H), 1.38 (sext, 2H), 1.69 (quint,2H), 2.33 (t, 2H), 3.2-3.9 (br, 8H), 4.20 (s, 2H), 4.35 (s, 1H), 6.69(s, 1H), 6.73 (d, 1H), 6.94 (d, 6H), 7.1-7.2 (m, 4H), 7.2-7.6 (m, 13H),7.90 (d, 1H)

Compound ( 1!-(16)-594')

¹ H-NMR (500 MHz, CDCl₃) δ: 0.88 (t, 3H), 1.34 (sext, 2H), 1.61 (quint,2H), 2.23 (t, 2H), 3.3-3.9 (br, 8H), 3.92 (s, 4H), 6.88 (d, 12H), 6.92(d, 4H), 7.05 (d, 4H), 7.14-7.35 (m, 22H), 7.43-7.51 (m, 4H), 7.91 (d,4H), 8.38 (d, 2H), 8.53 (s, 1H)

Example 5 Preparation of 3-(4-carboxyphenyl)methylamino!-4-valeramidobenzoic acid morpholide (1!-(16)-1) (Compound No. 1)

The compound ( 1!-(16)-1') (7.71 g) prepared in Example 3 was dissolvedin tetrahydrofuran (200 ml), and 1N NaOH aqueous solution (38 ml) anddistilled water (380 ml) were added. Then, the reaction mixture wasstirred at room temperature for 6.5 hours. After methanol was evaporatedfrom the reaction solution, the solution was adjusted to pH 5 with 1NHCl aqueous solution to obtain a precipitate. The precipitate waspurified by silica gel column chromatography (Kieselgel 60=100 g,chloroform/methanol=10/1) to obtain the compound ( 1!-(16)-1) (CompoundNo. 1) (5.79 g) as white foam.

Melting point: 109.0°-111.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 0.86 (t,3H), 1.36 (sext, 2H), 1.63 (quint, 2H), 2.37 (t, 2H), 2.9-3.8 (br, 8H),4.46 (d, 2H), 5.88 (t, 1H), 6.35 (s, 1H), 6.59 (d, 1H), 7.26 (d, 1H),7.46 (d, 2H), 7.89 (d, 2H), 9.25 (s, 1H)

Example 6 Preparation of 3-2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methylamino!-4-valeramidobenzoic acidmorpholide ( 1!-(16)-585) (Compound No. 585)

The compound ( 1!-(16)-585') (5.00 g) prepared in Example 4 wasdissolved in methanol (100 ml) and tertahydrofuran (10 ml). After themixture was cooled to -20° C., concentrated hydrochloric acid (30 ml)was slowly added dropwise. The reaction mixture was poured in a beakercontaining sodium hydroxide (30.0 g), water (40 ml), and ice (100 g),and the insolubles were removed. After the organic solvent of thereaction solution was evaporated, the insolubles were further removed.The solution was adjusted to pH 4-5 with 1N HCl aqueous solution forprecipitation to collect the precipitated crystals. The above procedurewas repeated twice. The resulting white crystals were purified by silicagel column chromatography (Kieselgel 60=100 g, chloroform/methanol=10/1)to obtain the compound ( 1!-(16)-585) (Compound No. 585) (4.09 g) aswhite foam.

Melting point: 131.0°-133.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 0.91 (t,3H), 1.36 (sext, 2H), 1.63 (quint, 2H), 2.37 (t, 2H), 3.0-3.8 (br, 8H),4.37 (d, 2H), 5.77 (t, 1H), 6.45 (s, 1H), 6.59 (d, 1H), 7.02 (d, 4H),7.21-7.69 (m, 5H), 9.21 (s, 1H)

Example 7 Preparation of 3- di-2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methylamino!-4-valeramidobenzoic acidmorpholide ( 1!-(16)-594) (Compound No. 594)

The compound ( 1!-(16)-594') (10.0 g) prepared in Example 4 wasdissolved in tertahydrofuran (200 ml). After 12% HCl aqueous solution(50 ml) was added, the reaction mixture was stirred at room temperaturefor 6 hours. After the solvent was evaporated, 1N NaOH aqueous solutionwas added and the insolubles were removed. The solution was adjusted topH 4-5 with 1N HCl aqueous solution to obtain a precipitate. Theresulting crystals were purified by silica gel column chromatography(Kieselgel 60=75 g, chloroform/methanol=10/1) to obtain the compound (1!-(16)-594) (Compound No. 594) (4.27 g) as white foam.

Melting point: 207.0°-210.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 0.83 (t,3H), 1.26 (sext, 2H), 1.50 (quint, 2H), 2.31 (t, 2H), 2.8-3.9 (br, 8H),4.10 (s, 4H), 6.9-7.1 (m, 6H), 7.29 (d, 4H), 7.48 (d, 2H), 7.5-7.7 (m,6H), 7.82 (d, 1H), 9.03 (s, 1H)

Example 8 Preparation of 4-n-amylamino-3,5-dinitrobenzoic acidmorpholide ( 1!-(12-593)

To a solution of 4-n-amylamino-3,5-dinitrobenzoic acid (23.80 g) inanhydrous tetrahydrofuran (360 ml), dicyclohexylcarbodiimide (21.47 g),1-hydroxybenzotriazole (14.06 g), and morpholine (9.1 ml) were added tothe solution. The mixture was stirred at room temperature for 14 hours.After the insolubles were filtered out and washed with tetrahydrofuran,the filtrate and the washing were combined and concentrated to obtain areddish brown solid (51.04 g). The solid was recrystallized from amixture of n-hexane (50 ml) and ethyl acetate (150 ml) to obtain thecompound ( 1!-(12)-593) (32.61 g) as yellowish orange needle crystals.

Melting point: 126.0°-129.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 0.85 (t,3H), 1.24-1.32 (m, 4H), 1.60-1.63 (m, 2H), 2.94 (dr, 2H), 3.53 (bs, 4H),3.61 (bs, 4H), 8.24 (t, 1H), 8.29 (s, 2H)

Example 9 Preparation of 4-(N-n-amyl-N-methyl)amino-3,5-dinitrobenzoicacid morpholide ( 1!-(13)-593)

The compound ( 1!-(12)-593) (5.00 g) prepared in Example 8 was dissolvedin N,N-dimethylformamide (75 ml). To the solution, methyl iodide (9.69g) and silver (I) oxide (6.33 g) were added, and the mixture was stirredat room temperature overnight. After the insolubles were filtered out,the reaction solution was poured into water (200 ml), and extracted withchloroform. The organic layer was washed with saturated brine, driedover anhydrous sodium sulfate, and concentrated under reduced pressureto obtain a crude product (8.21 g). The crude product was purified bysilica gel column chromatography (Kieselgel 60, chloroform/ethylacetate=6/1) to obtain the compound ( 1!-(13)-593) (2.22 g) as orangeoil. Further, the part including impurities was repurified to obtain thecompound ( 1!-(13)-593) (2.09 g)

¹ H-NMR (500 MHz, CDCl₃) δ: 0.88 (t, 3H), 1.20-1.35 (m, 4H), 1.99(bquint, 2H), 2.84 (s, 3H), 2.93 (t, 2H), 3.64-3.73 (br, 8H), 7.91 (s,2H)

Example 10 Preparation of 4-(N-n-amyl-N-methyl)amino-3,5-diaminobenzoicacid morpholide ( 1!-(14)-593)

The compound ( 1!-(13)-593) (2.22 g) prepared in Example 9 was dissolvedin methanol/ethyl acetate (1/9) (22 ml). To the solution, tin (II)chloride dihydrate (13.17 g) were added and the mixture was heated to80° C. and stirred for 30 minutes under an argon gas stream. Thereaction solution was poured into water (10 ml), adjusted toapproximately pH 7 with 5% sodium hydrogencarbonate aqueous solution andsodium carbonate, and the precipitated insolubles were filtered outthrough celite. The organic layer was concentrated, and the aqueouslayer was extracted with chloroform. The organic layer was washed withsaturated brine, and dried over anhydrous sodium sulfate to obtain acrude product (1.02 g).

The crude product was purified by silica gel column chromatography(Kieselgel 60, chloroform/methanol=15/1) to obtain the compound (1!-(14)-593) (0.84 g) as colorless oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.88 (t, 3H), 1.22-1.40 (m, 4H), 1.48(bquint, 2H), 2.76 (s, 3H), 2.97 (t, 2H), 3.48-4.03 (br, 12H), 6.10 (s,2H)

Example 11 Preparation of3-amino-4-(N-n-amyl-N-methyl)amino-5-(diphenylacetamido)benzoic acidmorpholide ( 1!-(15)-593)

To a solution of N,N-dicyclohexylcarbodiimide (0.54 g),1-hydroxybenzotriazole (0.35 g), and diphenylacetic acid (0.56 g) inacetonitrile (5 ml), a solution of the compound ( 1!-(14)-593) (0.80 g)prepared in Example 10 in acetonitrile (4 ml). The mixture was stirredovernight. The insolubles were filtered through celite, and the-filtratewas concentrated. The residue was dissolved in chloroform, and washedwith saturated sodium hydrogencarbonate aqueous solution. The chloroformlayer was dried over anhydrous sodium sulfate, and concentrated underreduced pressure to obtain a crude product (1.27 g).

The crude product was purified by silica gel column chromatography(Kieselgel 60, n-hexane/ethyl acetate=1/4) to obtain the compound (1!-(15)-593) (0.68 g) as light yellow crystals.

Melting point: 72.0°-5.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.85 (t, 3H),0.95-1.15 (m, 4H), 1.20 (quint, 2H), 2.39 (s, 3H), 2.50-2.60 (m, 1H),2.70-2.76 (m, 1H), 3.54-3.72 (br, 10H), 5.14 (s, 1H), 6.47 (s, 1H),7.28-7.39 (m, 10H), 7.95 (s, 1H), 8.94 (s, 1H)

Example 12 Preparation of4-(N-n-amyl-N-methyl)amino-5-(diphenylacetamido)-3-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methylamino!benzoicacid morpholide ( 1!-(16)-593')

The compound ( 1!-(15)-593) (0.25 g) prepared in Example 11 wasdissolved in benzene (10 ml), and N-(triphenylmethyl)-5-4'-(bromomethyl)biphenyl-2-yl!tetrazole (0.42 g) anddiisopropylethylamine (0.63 g) were added to the solution. The mixturewas heated to 80° C. and stirred for 2 days under an argon gas stream.Diisopropylethylamine (0.13 g) were added to the reaction mixture, andthe mixture was further heated and stirred for 3 days. The solvent wasconcentrated under reduced pressure, and the residue was extracted withchloroform. The organic layer was dried over anhydrous sodium sulfate,and concentrated under reduced pressure to obtain a crude product (0.76g). The crude product was purified by silica gel column chromatography(Kieselgel 60, chloroform/ethyl acetate=6/1) to obtain the compound (1!-(16)-593') (0.22 g) as light yellow crystals.

Melting point: 112.0°-115.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.83 (t,3H), 1.04-1.15 (m, 4H), 1.18 (bquint, 2H), 2.35 (s, 3H), 2.45-2.55 (m,1H), 2.60-2.70 (m, 1H), 3.53-3.71 (br, 9H), 4.21 (s, 2H), 5.15 (s, 1H),6.44 (s, 1H), 6.92-7.18 (m, 10H), 7.21-7.44 (m, 20H), 7.45-7.51 (m, 2H),7.89-7.92 (m, 2H), 8.60 (s, 1H)

Example 13 Preparation of4-(N-n-amyl-N-methyl)amino-5-(diphenylacetamido)-3-2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methylamino!benzoic acid morpholide (1!-(16)-593) (Compound No. 593)

The compound ( 1!-(16)-593') (0.15 g) prepared in Example 12 wasdissolved in tetrahydrofuran (3 ml), and 12% HCl aqueous solution (0.75ml) was added to the solution. The mixture was stirred at roomtemperature overnight. The reaction solution was adjusted to pH 7 with5% sodium carbonate aqueous solution, and extracted with ethyl acetate.The organic layer was washed with saturated brine, and concentratedunder reduced pressure to obtain a crude product (0.17 g). The crudeproduct was purified by silica gel column chromatography (Kieselgel 60,ethyl acetate) to obtain the compound ( 1!-(16)-593) (Compound No. 593)(0.050 g).

Melting point: 122.0°-125.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.86 (t,3H), 1.12 (bs, 4H), 1.25 (bquint, 2H), 2.46 (s, 3H), 2.55-2.65 (m, 1H),2.65-2.75 (m, 1H), 3.52-3.71 (br, 9H), 4.45 (s, 2H), 5.16 (s, 1H), 6.07(s, 1H), 7.06 (d, 2H), 7.17 (d, 2H), 7.30-7.41 (m, 11H), 7.45-7.60 (m,3H), 7.80 (s, 1H), 7.97 (d, 1H), 8.52 (s, 1H)

Example 14 Preparation of 4-(4-chloro-3,5-dinitrobenzene)sulfonyl!morpholine ( 2!-(22)-598)

Morpholine (0.89 g) was dissolved in dichloromethane (20 ml), andtriethylamine (1.41 ml) was added. The mixture was cooled on ice. To thesolution, a solution of 3,5-dinitro-4-chloro-benzenesulfonyl chloride (2!-(21)-598) (2.56 g) in dichloromethane (15 ml) was added dropwise. Themixture was stirred for 4.5 hours, and extracted with chloroform. Theorganic layer was dried over anhydrous sodium sulfate, and the solventwas evaporated. The crude product was purified by silica gel columnchromatography (Kieselgel 60=50 g, chloroform) to obtain the compound (2!-(22)-598) (0.32 g).

¹ H-NMR (500 MHz, CDCl₃) δ: 3.15 (t, 4H), 3.80 (t, 4H), 8.30 (s, 2H)

Example 15 Preparation of 4-(4-n-amylamino-3,5-dinitrobenzene)sulfonyl!morpholine ( 2!-(23)-598)

A mixture of the compound ( 2!-(22)-598) (0.26 g) prepared in Example14, acetone (5 ml), amylamine (0.1 ml), and water (5 ml) was heatedunder reflux overnight. The solvent was evaporated from the reactionmixture, and the residue was extracted with chloroform. The organiclayer was dried over anhydrous sodium sulfate, and the solvent wasevaporated. The crude product was purified by silica gel columnchromatography (Kieselgel 60=50 g, chloroform) to obtain the compound (2!-(23)-598) (0.27 g).

¹ H-NMR (500 MHz, CDCl₃) δ: 0.93 (t, 3H), 1.34-1.40 (m, 4H), 1.73(quint, 2H), 3.05 (t, 2H), 3.08 (t, 4H), 3.78 (t, 4H), 8.47 (s, 2H),8.79 (bs, 1H)

Example 16 Preparation of 4-4-(N-n-amyl-N-methyl)amino-3,5-dinitrobenzene!sulfonyl!morpholine (2!-(24)-598)

The compound ( 2!-(23)-598) (1.59 g) prepared in Example 15 wasdissolved in N,N-dimethylformamide (15 ml), and methyl iodide (2.81 g)and silver (I) oxide (1.84 g) were added. The mixture was stirredovernight. The reaction solution was filtered through celite, and waswashed with ethyl acetate, 1N HCl aqueous solution and then saturatedbrine. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated. The crude product was purified by silica gelcolumn chromatography (Kieselgel 60=85 g, chloroform) to obtain thecompound ( 2!-(24)-598) (1.32 g) as a yellow solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.89 (t, 3H), 1.2-1.33 (m, 4H), 1.65 (quint,2H), 2.88 (s, 3H), 2.98 (bt, 2H), 3.09 (t, 4H), 3.78 (t, 4H), 8.12 (s,2H)

Example 17 Preparation of 4-3,5-diamino-4-(N-n-amyl-N-methyl)aminobenzene!sulfonyl!morpholine (2!-(25)-598)

To a solution of the compound ( 2!-(24)-598) (2.16 g) prepared inExample 16 in ethyl acetate (70 ml), tin (II) chloride dihydrate (11.7g) was added. The mixture was reacted at 90° C. for 30 minutes under anitrogen gas stream. To the reaction solution, water (10 ml) was added,and sodium hydrogencarbonate was added to neutralize the solution. Thesolution was filtered through celite, and washed with ethyl acetate. Thefiltrate was washed with brine. The organic layer was dried overanhydrous sodium sulfate, and the solvent was evaporated. The crudeproduct (2.12 g) was purified by silica gel column chromatography(Kieselgel 60=125 g, chloroform) to obtain the compound ( 2!-(25)-598)(0.57 g)

¹ H-NMR (500 MHz, CDCl₃) δ: 0.89 (t, 3H), 1.20-1.35 (m, 4H), 1.49(quint, 2H), 2.77 (s, 3H), 2.99 (bt, 2H), 3.03 (t, 4H), 3.74 (t, 4H),4.04 (s, 4H), 6.44 (s, 2H)

Example 18 Preparation of 4-3-amino-4-(N-n-amyl-N-methyl)amino-5-(diphenylacetamido)benzene!sulfonyl!morpholine-(2!-(26)-598)

To a solution of diphenylacetic acid (0.41 g) in tetrahydrofuran (3 ml),dicyclohexylcarbodiimide (0.37 g) and 1-hydroxybenzotriazole (0.26 g)were added. After 10 minutes, a solution of the compound ( 2!-(25)-598)prepared in Example 17 in chloroform (6 ml) was added dropwise, and themixture was stirred at room temperature overnight. The insolubles werefiltered, and the filtrate was concentrated. To the concentrate, ethylacetate (30 ml) was added. The organic layer was washed with 1N NaOHaqueous solution, and dried over anhydrous sodium sulfate. Then thesolvent was evaporated. The crude product was purified by silica gelcolumn chromatography (Wako-gel C300=75 g, chloroform) to obtain a whitesolid ( 2!-(26)-598) (0.75 g)

¹ H-NMR (500 MHz, CDCl₃) δ: 0.86 (t, 3H), 1.00-1.15 (br, 4H), 1.22(bquint, 2H), 2.40 (s, 3H), 2.57-2.59 (m, 1H), 2.60-2.70 (m, 1H), 3.09(bt, 4H), 3.74 (t, 4H), 3.81 (s, 2H), 5.15 (s, 1H), 6.79 (d, 1H),7.29-7.39 (m, 10H), 8.28 (s, 1H), 8.88 (s, 1H)

Example 19 Preparation of 4-3amino-4-(N-n-amyl-N-methyl)amino-5-(3-phenylpropionamido)benzene!sulfonyl!morpholine( 2!-(26)-599)

To a solution of 3-phenylpropionic acid (3.32 g) inN,N-dimethylformamide (30 ml), dicyclohexylcarbodiimide (3.96 g) and1-hydroxybenzotriazole (2.99 g) were added. After 2 hours, a solution ofthe compound ( 2!-(25)-598) (6.84 g) prepared in Example 17 inN,N-dimethylformamide (15 ml) was added dropwise. After the mixture wasstirred at room temperature overnight, the insolubles were filtered, andthe filtrate was concentrated. To the concentrate, ethyl acetate (30 ml)was added, and the organic layer was washed with 1N NaOH aqueoussolution, and dried over anhydrous sodium sulfate. Then the solvent wasevaporated. The crude product was purified by silica gel columnchromatography (Kieselgel 60=250 g, chloroform) to obtain a white solid( 2!-(26)-599) (7.02 g)

¹ H-NMR (500 MHz, CDCl₃) δ: 0.88 (t, 3H), 1.26-1.43 (m, 6H), 2.67 (s,3H), 2.73 (t, 2H), 2.90-3.00 (m, 2H), 3.06 (t, 2H), 3.09 (t, 4H), 3.74(t, 4H), 3.90 (s, 2H), 6.79 (d, 1H), 7.19-7.31 (m, 5H), 8.20 (s, 1H),8.71 (s, 1H)

Example 20 Preparation of 4- 4-(N-n-amyl-N-methyl)amino-3-(4-methoxycarbonylphenyl)methyl!amino-5-(diphenylacetamido)benzene!sulfonyl!morpholine( 2!-(27)-598')

A mixture of the compound ( 2!-(26)-598) (0.08 g) prepared in Example18, methyl 4-bromomethylbenzoate (0.07), triethylamine (0.04 ml), andtoluene (5 ml) was stirred at 80° C. for 48 hours under a nitrogen gasatmosphere. The solvent was evaporated, and the residue was purified bysilica gel column chromatography (Wako-gel C300=25 g, chloroform) toobtain a white solid ( 2!-(27)-598') (0.07 g).

¹ H-NMR (500 MHz, CDCl₃) δ: 0.86 (t, 3H), 1.00-1.15 (m, 4H), 1.22(bquint, 2H), 2.42 (s, 3H), 2.50-2.60 (m, 1H), 2.61-2.64 (m, 1H), 2.81(bs, 4H), 3.62 (t, 4H), 3.90 (s, 3H), 4.44 (d, 2H), 4.63 (bt, 1H), 5.15(s, 1H), 6.57 (s, 1H), 7.28-7.39 (m, 12H), 7.98 (d, 2H), 8.18 (s, 1H),8.46 (s, 1H)

Example 21 Preparation of 4- 4-(N-n-amyl-N-methyl)amino-3-(4-carboxylphenyl)methyl!amino-5-(diphenylacetamido)benzene!sulfonyl!morpholine( 2!-(27)-598) (Compound No. 598)

The compound ( 2!-(27)-598') (0.06 g) prepared in Example 20 wasdissolved in methanol (5 ml), and 1N NaOH aqueous solution (0.3 ml) wasadded. The mixture was stirred overnight. Further, 1N NaOH aqueoussolution (0.2 ml) was added, and the mixture was stirred for 4 days. Thereaction solution was concentrated, and adjusted to pH 1 with 1N HClaqueous solution. The precipitated solid was filtered out. The solid wastreated by a preparative thin layer chromatography (Merck 13895,chloroform/methanol=10/1) to obtain a white solid ( 2!-(27)-598)(Compound No. 598) (0.03 g).

¹ H-NMR (500 MHz, CDCl₃) δ: 0.87 (t, 3H), 1.10 (bs, 4H), 1.23 (bquint,2H), 2.43 (s, 3H), 2.50-2.60 (m, 1H), 2.60-2.70 (m, 1H), 2.81 (bs, 4H),3.62 (t, 4H), 4.47 (bd, 2H), 4.65 (bs, 1H), 5.16 (s, 1H), 6.56 (d, 1H),7.30-7.41 (m, 12H), 8.03 (d, 2H), 8.19 (s, 1H), 8.45 (s, 1H)

Example 22 Preparation of 4- 4-(N-n-amyl-N-methyl)amino-3-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methyl!amino-5-(3-phenylpropionamido)benzene!sulfonyl!morpholine( 2!-(27)-599')

A mixture of the compound ( 2!-(26)-599) (7.01 g) prepared in Example19, diisopropylethylamine (7.60 g), N-(triphenylmethyl)-5-4'-(bromomethyl)biphenyl-2-yl!tetrazole (12.6 g), and toluene (150 ml)was stirred at 80° C. for 4 days under a nitrogen gas atmosphere. Afterthe reaction mixture was concentrated, the mixture was extracted withchloroform. The organic layer was dried, and concentrated. The crudeproduct (20.1 g) was purified by silica gel column chromatography(Kieselgel 60=300 g, chloroform) to obtain a white solid ( 2!-(27)-599')(3.13 g).

¹ H-NMR (500 MHz, CDCl₃) δ: 0.85 (t, 3H), 1.23-1.31 (m, 4H), 1.35-1.50(m, 2H), 2.66 (s, 3H), 2.69 (t, 2H), 2.93 (bt, 4H), 2.98 (t, 2H), 3.07(dd, 2H), 3.65 (t, 4H), 4.27 (d, 2H), 4.41 (bs, 1H), 6.23 (d, 1H), 6.94(d, 4H), 7.05-7.46 (m, 21H), 7.47-7.52 (m, 2H), 7.90 (d, 1H), 8.10 (s,1H), 8.35 (s, 1H)

Example 23 Preparation of 4- 4-(N-n-amyl-N-methyl) amino-3-2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!amino-5-(3-phenylpropionamido)benzene!sulfonyl!morpholine( 2!-(27)-599) (Compound No. 599)

The compound ( 2!-(27)-599') (3.13 g) prepared in Example 22 wasdissolved in tetrahydrofuran (35 ml), and concentrated hydrochloric acid(17 ml) was added dropwise to the solution. After the mixture wasstirred at room temperature for 4 hours, the mixture was adjusted to pH7 with 10N NaOH aqueous solution, and extracted with chloroform. Afterthe organic layer was dried over anhydrous sodium sulfate, theconcentrated crude product was purified by silica gel columnchromatography (Wako-gel C300=100 g, chloroform/methanol=10/1) to obtaina white solid ( 2!-(27)-599) (Compound No. 599) (1.43 g).

¹ H-NMR (500 MHz, CDCl₃) δ: 0.89 (t, 3H), 1.30-1.50 (m, 4H), 1.40-1.50(m, 2H), 2.69 (t, 2H), 2.68 (t, 2H), 2.74 (s, 3H), 2.88 (bs, 4H),2.96-3.04 (m, 2H), 3.07 (t, 2H), 3.67 (t, 4H), 4.49 (d, 2H), 4.82 (bs,1H), 6.47 (d, 1H), 7.15 (d, 2H), 7.21-7.31 (m, 6H), 7.47-7.62 (m, 2H),7.93 (d, 2H), 8.09 (s, 1H), 8.30 (s, 1H)

Example 24 Preparation of 4-(4-chloro-3-nitrobenzene)sulfonyl!morpholine ( 2!-(22)-596)

To a solution of 4-chloro-3-nitrobenzenesulfonyl chloride (0.26 g) indichloromethane (1.0 ml), morpholine (1.80 g) and dichloromethane (1.0ml) were added at 0° C., and dissolved. The reaction solution wasstirred at room temperature for 5 hours. Distilled water was added tothe reaction solution, and the reaction mixture was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulfate, and concentrated to obtain yellow crystals. The crystals werepurified by silica gel column chromatography (Kieselgel 60, hexane/ethylacetate=1/1) to obtain the compound ( 2!-(22)-596) (0.29 g) as lightyellow crystals.

Melting point: 146.0°-148.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 3.08 (t,4H), 3.78 (t, 4H), 7.77 (d, 1H), 7.88 (dd, 1H), 8.23 (d, 1H)

Example 25 Preparation of 4-(4-n-amylamino-3-nitrobenzene)sulfonyl!morpholine ( 2!-(23)-596)

To a mixture of the compound ( 2!-(22)-596) (9.62 g) prepared in Example24, tetrahydrofuran (10 ml), and ethanol (20 ml), a solution ofn-amylamine (5.47 g) in ethanol (20 ml) was added at room temperature,and the mixture was heated under reflux at 70° C. for 4 hours. Thereaction mixture was concentrated under reduced pressure, and extractedwith chloroform. The organic layer was washed with distilled water,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to obtain a crude product (12.36 g). The crude product waspurified by silica gel column chromatography (Kieselgel 60, hexane/ethylacetate=2/1) to obtain the compound ( 2!-(23)-596) (11.38 g) as yellowcrystals.

Melting point: 74.5°-76.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.95 (t, 3H),1.40-1.52 (m, 4H), 1.78 (quint, 2H), 3.03 (t, 4H), 3.36 (dd, 2H), 3.76(t, 4H), 6.96 (d, 1H), 7.73 (dd, 1H), 8.40 (bs, 1H), 8.58 (d, 1H)

Example 26 Preparation of 4-4-(N-n-amyl-N-methyl)amino-3-nitrobenzene!sulfonyl!morpholine (2!-(24)-596)

The compound ( 2!-(23)-596) (0.40 g) prepared in Example 25 wasdissolved in N,N-dimethylformamide (2 ml), and methyl iodide (0.79 g)and silver (I) oxide (0.52 g) were added. The mixture was stirred atroom temperature overnight. After the insolubles were filtered out, thefiltrate was concentrated under reduced pressure, and the residue wasextracted with chloroform. The organic layer was washed with distilledwater, dried over anhydrous sodium sulfate, and concentrated underreduced pressure. The crude product was purified by silica gel columnchromatography (Kieselgel 60, hexane/ethyl acetate=1/1) to obtain thecompound ( 2!-(24)-596) (0.47 g) as yellow crystals.

Melting point: 99.5°-101.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.92 (t, 3H),1.25-1.38 (m, 4H), 1.68 (quint, 2H), 2.89 (s, 3H), 3.02 (t, 4H), 3.28(t, 2H), 3.76 (t, 4H), 7.08 (d, 1H), 7.65 (dd, 1H), 8.12 (d, 1H)

Example 27 Preparation of 4-3-amino-4-(N-n-amyl-N-methyl)aminobenzene!sulfonyl!morpholine (2!-(25)-596)

A mixture of the compound ( 2!-(24)-596) (3.57 g) prepared in Example26, ethyl acetate (52.9 ml), methanol (8.9 ml), and tin (II) chloridedihydrate (10.9 g) was heated under reflux at 80° C. for 1 hour under anitrogen gas stream. The reaction solution was cooled, and neutralized(pH=approximately 6) with 5% sodium carbonate aqueous solution. Thesolution was filtered through celite, and concentrated. The residue wasextracted with ethyl acetate. The organic layer was washed withdistilled water, and dried over anhydrous sodium sulfate. The solventwas evaporated. The crude product (3.17 g) was purified by silica gelcolumn chromatography (Kieselgel 60, hexane/ethyl acetate=1/1) to obtainthe compound ( 2!-(25)-596) (0.31 g) as colorless crystals.

Melting point: 83.0°-84.5° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.89 (t, 3H),1.28-1.35 (m, 4H), 1.52 (quint, 2H), 2.67 (s, 3H), 2.88 (t, 2H), 3.00(t, 4H), 3.74 (t, 4H), 4.14 (s, 2H), 7.04-7.10 (m, 3H)

Example 28 Preparation of 4- 4-(N-n-amyl-N-methyl)amino-3-(4-methoxycarbonylphenyl!methyl!aminobenzene!sulfonyl!morpholine (2!-(27)-596')

To a solution of the compound ( 2!-(25)-596) (0.10 g) prepared inExample 27 and methyl 4-bromomethylbenzoate (0.10 g) in dichloromethane(3 ml), diisopropylethylamine (0.57 g) was added, and the reactionmixture was heated under reflux at 40° C. for 2 days. The reactionsolution was concentrated under reduced pressure, and the residue wasextracted with chloroform. The organic layer was washed with distilledwater, dried over anhydrous sodium sulfate, and concentrated underreduced pressure to obtain yellow oil. The oil was purified by silicagel column chromatography (Kieselgel 60, hexane/ethyl acetate=4/1) toobtain the compound ( 2!-(27)-596') (0.13 g) as yellow oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.88 (t, 3H), 1.24-1.31 (m, 4H), 1.51 (bt,2H), 2.68 (s, 3H), 2.72 (t, 4H), 2.89 (t, 2H), 3.61 (t, 4H), 3.90 (s,3H), 4.48 (d, 2H), 5.36 (s, 1H), 6.70 (d, 1H), 7.04 (dd, 1H), 7.08 (d,1H), 7.41 (d, 2H), 8.00 (d, 2H)

Example 29 Preparation of 4- 4-(N-n-amyl-N-methyl)amino-3-(4-carboxyphenyl)methyl!aminobenzene!sulfonyl!morpholine ( 2!-(27)-596)(Compound No. 596)

To a solution of the compound ( 2!-(27)-596') (0.13 g) prepared inExample 28 in dimethoxyethane (12 ml), 0.1N NaOH aqueous solution (5.2ml) was added, and the reaction mixture was stirred at room temperatureovernight. The reaction mixture was adjusted to pH 7 with 0.1N HClaqueous solution, and concentrated under reduced pressure to obtainyellow oil (0.15 g). The oil was purified by silica gel columnchromatography (Kieselgel 60, chloroform/methanol=10/1) to obtain thecompound ( 2!-(27)-596) (Compound No. 596) (0.09 g) as colorlesscrystals.

Melting point: 182.5°-186.0° C. ¹ H-NMR (500 MHz, CD₃ OD) δ: 0.89 (t,3H), 1.33 (bquint, 4H), 1.55 (bt, 2H), 2.49 (t, 4H), 2.73 (s, 3H), 3.00(t, 2H), 3.51 (t, 4H), 4.55 (s, 2H), 6.59 (d, 1H), 6.96 (dd, 1H), 7.16(d, 1H), 7.45 (d, 2H), 7.95 (d, 2H)

Example 30 Preparation of 4- 4-(N-n-amyl-N-methyl)amino-3-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methyl!aminobenzene!sulfonyl!morpholine( 2!-(27)-595')

To a solution of the compound ( 2!-(25)-596) (0.15 g) prepared inExample 27 and N-(triphenylmethyl)-5-4-(bromomethyl)biphenyl-2-yl!tetrazole (0.50 g) in benzene (5 ml),diisopropylethylamine (0.59 g) was added, and the reaction mixture wasrefluxed at 80° C. for 6 days. The reaction mixture was concentratedunder reduced pressure, and the residue was extracted with chloroform.The organic layer was washed with distilled water, dried over anhydroussodium sulfate, and concentrated under reduced pressure to obtain yellowoil (0.69 g). The oil was purified by silica gel column chromatography(Kieselgel 60, chloroform/ethyl acetate=30/1) to obtain the compound (2!-(27)-595') (0.21 g) as yellow oil.

Example 31 Preparation of 4- 4-(N-n-amyl-N-methyl)amino-3-2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!aminobenzene!sulfonyl!morpholine( 2!-(27)-595) (Compound No. 595)

To a solution of the compound ( 2!-(27)-595') (0.39 g) prepared inExample 30 in tetrahydrofuran (7.7 ml), 12% HCl aqueous solution (1.9ml) was further added, and the reaction mixture was stirred at roomtemperature for 5 hours. The reaction mixture was adjusted to pH 5 with5% sodium carbonate aqueous solution, and concentrated under reducedpressure. The residue was extracted with ethyl acetate. The organiclayer was washed with distilled water, dried over anhydrous sodiumsulfate, and concentrated under reduced pressure to obtain yellow oil(0.38 g). The oil was purified by silica gel column chromatography(Kieselgel 60, chloroform/methanol=20/1) to obtain the compound (2!-(27)-595) (Compound No. 595) (0.19 g) as white foam.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.89 (t, 3H), 1.32 (bquint, 4H), 1.55 (bs,2H), 2.71 (s, 3H), 2.76 (s, 4H), 2.92 (t, 2H), 3.70 (t, 4H), 4.51 (d,2H), 5.53 (t, 1H), 6.63 (s, 1H), 7.05-7.09 (m, 2H), 7.14 (d, 2H), 7.29(d, 1H), 7.47-7.54 (m, 2H), 7.60-7.63 (m, 1H), 7.90 (d, 1H)

Example 32 Preparation of (3-nitro-4-valeramido)benzoic aciddiethylamide ( 1!-(12)-586)

In dry N,N-dimethylformamide (300 ml), 3-nitro-4-valeramidobenzoic acid(19.35 g) was dissolved, and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (16.74 g),1-hydroxybenzotriazole (11.80 g), diethylamine (11.88 g), andtriethylamine (8.83 g) were added successively. The reaction mixture wasstirred at room temperature for 36 hours, and the solvent was evaporatedin a bath at 80° C. under reduced pressure to a solution volume ofapproximately 100 ml. After ethyl acetate (400 ml) was added to theresidue, the mixture was washed with 1N HCl aqueous solution (100 ml),water (200 ml), saturated sodium carbonate aqueous solution (50 ml), andwater (150 ml) successively. The organic layer was dried over anhydrousmagnesium sulfate to obtain the compound ( 1!-(12)-586) (23.64 g) aslight yellow oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.90 (t, 3H), 1.14 (bs, 6H), 1.36 (sext,2H), 1.68 (quint, 2H), 2.44 (t, 2H), 3.23 (bs, 2H), 3.45 (bs, 2H), 7.59(d, 1H), 8.21 (s, 1H), 8.77 (d, 1H), 10.33 (s, 1H)

Example 33 Preparation of (3-amino-4-valeramido)benzoic aciddiethylamide ( 1!-(14)-586)

The compound ( 1!-(12)-586) (23.64 g) prepared in Example 32 wasdissolved in ethanol (800 ml). After the solution was stirred at 60° C.for 30 minutes, a suspension of 10% Pd/C (0.88 g) in ethanol (2 ml) wasadded to the solution, and hydrazine monohydrate (7.15 ml) was addeddropwise over 5 minutes. After the solution was stirred at the sametemperature for 30 minutes, it was cooled, and the insolubles werefiltered out through celite. The filtrate was concentrated to obtain acolorless solid (20.69 g). The solid was dissolved in chloroform (300ml), washed with water (100 ml), dried over anhydrous magnesium sulfate,and concentrated to obtain the compound ( 1!-(14)-586) (19.96 g) as acolorless solid.

Melting point: 121.0°-123.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.96 (t,3H), 1.06 (bs, 3H), 1.23 (bs, 3H), 1.42 (sext, 2H), 1.72 (quint, 2H),2.44 (t, 2H), 3.24 (bs, 2H), 3.51 (bs, 2H), 6.47 (d, 1H), 6.53 (s, 1H),6.87 (d, 1H), 8.83 (s, 1H)

Example 34 Preparation of 3-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methylamino!-4-valeramido!benzoicacid diethylamide ( 1!-(16)-586')

The compound ( 1!-(14)-586) (9.64 g) prepared in Example 33 wasdissolved in chloroform (150 ml). N-(triphenylmethyl)-5-4'-(bromomethyl)biphenyl-2-yl!tetrazole (20.23 g) anddiisopropylethylamine (42.67 g) were added to the solution, and thereaction mixture was heated to the reflux temperature over 10 minutes.After the mixture was heated under reflux with stirring for 2.5 hoursand then cooled, chloroform (300 ml) was added to the mixture, and themixture was washed with water (250 ml), dried over anhydrous magnesiumsulfate, and concentrated to obtain colorless foam (36.22 g). Theproduct was purified by silica gel column chromatography (Kieselgel60=1200 g, chloroform/ethyl acetate=3/1) to obtain the compound (1!-(16)-586') (17.75 g) as colorless foam.

Melting point: 100.0°-105.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.90 (bs,3H), 0.91 (t, 3H), 1.20 (bs, 3H), 1.38 (sext, 2H), 1.70 (quint, 2H),2.38 (t, 2H), 3.14 (bs, 2H), 3.47 (bs, 2H), 4.14 (bs, 2H), 4.46 (bs,1H), 6.51 (bs, 1H), 6.54 (d, 1H), 6.92-6.95 (m, 7H), 7.02 (d, 1H),7.07-7.34 (m, 13H), 7.43-7.50 (m, 2H), 7.89 (d, 1H), 8.22 (s, 1H)

Example 35 Preparation of 3-2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methylamino!-4-valeramido!benzoicacid diethylamide ( 1!-(16)-586) (Compound No. 586)

While maintaining at -20° C. to -10° C., concentrated hydrochloric acid(80 ml) was added dropwise over 20 minutes to a solution of the compound( 1!-(16)-586') (5.26 g) prepared in Example 34, methanol (10 ml), andTHF (200 ml). The mixture was further stirred at the same temperaturefor 30 minutes, and poured into a solution of ice (250 g), sodiumhydroxide (56 g), and water (200 ml). The mixture was adjusted to pH 9with concentrated hydrochloric acid, and the precipitated viscousproduct was filtered out. The filtrate was filtered through celite, andadjusted to pH 3 with concentrated hydrochloric acid. The precipitatedsolid was filtered to obtain the compound (1.93 g) as a colorless solid.To the above viscous product which had been filtered out, 1N NaOHaqueous solution was added to pH 10. After water (1500 ml) was added,the solution was filtered through celite. The filtrate was adjusted topH 4, and the precipitated solid was filtered out to obtain the compound( 1!-(16)-586) (Compound No. 586) (1.31 g) (3.24 g in total) as acolorless solid.

Melting point: 137.0°-140.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 0.81 (bs,3H), 0.91 (t, 3H), 1.06 (bs, 3H), 1.35 (sext, 2H), 1.60 (quint, 2H),2.37 (t, 2H), 3.03 (bs, 2H), 3.32 (bs, 2H), 4.35 (s, 2H), 5.78 (bs, 1H),6.38 (s, 1H), 6.50 (d, 1H), 7.05 (d, 1H), 7.21 (d, 1H), 7.30 (d, 1H),7.50-7.69 (m, 4H), 9.25 (s, 1H)

Example 36 Preparation of 3-hydroxy-4-nitrobenzoic acid morpholine (3!-(32)-587)

To a solution of 3-hydroxy-4-nitrobenzoic acid (10.00 g) in dryN,N-dimethylformamide (150 ml),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.56 g),1-hydroxybenzotriazole (8.86 g), triethylamine (7.18 g), and morpholine(5.71 g) were added successively. A mixture was stirred at roomtemperature for 23 hours, and the solvent was evaporated in a bath at80° C. under reduced pressure to a solution volume of approximately 100ml. Ethyl acetate (400 ml) was added to the residue, and the mixture waswashed with 1N HCl aqueous solution (100 ml), water (200 ml), saturatedsodium carbonate aqueous solution (50 ml), and water (150 ml). Theorganic layer was dried over anhydrous magnesium sulfate, andconcentrated to obtain the compound ( 3!-(32)-578) (7.89 g) as a yellowsolid.

Melting point: 110.0°-115.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 3.39 (bs,2H), 3.64 (bs, 2H), 3.79 (bs, 4H), 7.01 (d, 1H), 7.18 (s, 1H), 8.17 (d,1H), 10.61 (s, 1H)

Example 37 Preparation of 3-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methyloxy!-4-nitrobenzoicacid morpholide ( 3!-(33)-587)

The compound ( 3!-(32)-587) (0.99 g) prepared in Example 36 wasdissolved in dry N,N-dimethylformamide (19 ml), and 50% sodium hydride(0.20 g) was added to the solution. The mixture was stirred at roomtemperature for 15 minutes. A solution of N-(triphenylmethyl)-5-4'-(bromomethyl)biphenyl-2-yl!tetrazole (2.19 g) inN,N-dimethylformamide (6.5 ml) was added to the solution. The mixturewas stirred at room temperature for 39 hours. The reaction mixture wasadded to water (50 ml), and extracted with chloroform (100 ml). Theorganic layer was washed, dried over anhydrous sodium sulfate, andconcentrated to obtain the compound (2.72 g) as a light yellow solid.The product was purified by silica gel column chromatography (Kieselgel60=190 g, chloroform/ethyl acetate=7/3) to obtain the compound (3!-(33)-587) (1.41 g)

Melting point: 188.0°-190.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 3.29 (bs,2H), 3.53 (bs, 2H), 3.76 (bs, 4H), 5.16 (s, 2H), 6.91-6.93 (m, 6H), 7.03(d, 1H), 7.14-7.16 (m, 3H), 7.20 (d, 1H), 7.24-7.34 (m, 10H), 7.38 (d,1H), 7.45-7.52 (m, 2H), 7.87 (d, 1H), 7.93 (d, 1H)

Example 38 Preparation of 3-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methyloxy!-4-aminobenzoicacid morpholide ( 3!-(34)-587)

A solution of the compound ( 3!-(33)-587) (0.60 g) prepared in Example37, ethanol (150 ml), and ethyl acetate (40 ml) was stirred at 70° C.for 15 minutes. After 10% Pd/C (0.10 g) and hydrazine monohydrate (1 ml)were added to the solution, the mixture was stirred at 70° C. for 1hour. The insolubles were filtered through celite, and the filtrate wasconcentrated to obtain colorless foam (0.67 g). The product was purifiedby silica gel column chromatography (Kieselgel 60=80 g, chloroform/ethylacetate=13/7) to obtain the compound ( 3!-(34)-587) (0.09 g).

Melting point: 95.0°-105.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 1.57 (bs,1H), 3.63 (bs, 4H), 3.67 (bs, 4H), 3.93 (bs, 1H), 4.98 (s, 2H), 6.66 (d,1H), 6.89-6.92 (m, 7H), 7.03 (s, 1H), 7.14-7.33 (m, 13H), 7.39 (d, 1H),7.46-7.53 (m, 2H), 7.96 (d, 1H)

Example 39 Preparation of 3-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methyloxy!-4-valeramidobenzoicacid morpholide ( 3!(35)-587')

The compound ( 3!-(34)-587) (0.07 g) prepared in Example 38 and4-dimethylaminopyridine (0.01 g) were dissolved in dry pyridine (1 ml).Valeryl chloride (0.043 g) was added dropwise by a syringe while coolingon ice. The mixture was stirred at room temperature for 2 hours, then,poured into water (20 ml), extracted with chloroform (10 ml) twice, anddried over anhydrous magnesium sulfate. The solvent was evaporated underreduced pressure to obtain the compound ( 3!-(35)-587') (0.08 g) as alight yellow solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.89 (t, 3H), 1.34 (sext, 2H), 1.64 (quint,2H), 2.27 (t, 2H), 3.67 (bs, 8H), 5.05 (s, 2H), 6.93-6.95 (m, 7H), 7.02(d, 1H), 7.11 (s, 1H), 7.15-7.35 (m, 12H), 7.40 (d, 1H), 7.47-7.54 (m,2H), 7.79 (s, 1H), 7.93 (d, 1H), 8.63 (bs, 1H)

Example 40 Preparation of 3-2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyloxy!-4-valeramidobenzoic acidmorpholide ( 3!-(35)-587) (Compound No. 587)

To a solution of the compound ( 3!-(35)-587') (0.069 g) prepared inExample 39, methanol (2 ml), and THF (5 ml), concentrated hydrochloricacid (1 ml) was added dropwise. The mixture was stirred at roomtemperature for 1 hour, poured into 1N NaOH aqueous solution (20 ml),and allowed to stand overnight. The solvent was evaporated at 50° C.under reduced pressure to a solution volume of approximately 20 ml, andthe precipitated solid was filtered out. To the filtrate, 1N HCl aqueoussolution was added until pH 2 and the precipitated solid was filteredout to obtain a colorless solid (0.035 g). The product was purified bysilica gel column chromatography (Kieselgel 60=5 g,chloroform/methanol=5/1) to obtain the Compound No. 587 (0.030 g) as acolorless solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.96 (t, 3H), 1.43 (sext, 2H), 1.73 (quint,2H), 2.44 (t, 2H), 3.40-3.80 (br, 8H), 5.28 (s, 2H), 6.77 (s, 1H), 6.95(d, 1H), 7.11 (d, 2H), 7.21 (d, 2H), 7.46-7.59 (m, 4H), 7.91 (s, 1H),7.97 (bs, 1H), 8.38 (d, 1H)

Example 41 Preparation of 4-amino-3-nitrobenzoic acid morpholide (4!-(42)-592)

A mixture of 4-amino-3-nitrobenzoic acid (7.40 g),1-hydroxybenzotriazole (6.59 g), dicyclohexylcarbodiimide (10.90 g), dryN,N-dimethylformamide (74 ml), and morpholine (4.3 ml) was stirred atroom temperature for 2 hours. The insolubles were filtered out, andwashed with N,N-dimethylformamide. The filtrate and the washing werecombined, and concentrated to obtain a yellowish brown solid (16.01 g).

Melting point: 184.0°-189.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO ) δ:3.50-3.58 (m, 4H), 3.59-3.60 (m, 4H), 7.04 (d, 1H), 7.47 (dd, 1H), 8.03(d, 1H)

Example 42 Preparation of 4-acetamido-3-nitrobenzoic acid morpholide (4!-(43)-592)

The compound ( 4!-(42)-592) (18.37 g) prepared in Example 41 anddimethylaminopyridine (5.67 g) were dissolved in dry pyridine (370 ml).The solution was stirred while cooling on ice under a nitrogen gasatmosphere, and acetyl chloride (9.9 ml) was added dropwise over 5minutes. Then, the mixture was stirred on an oil bath at 65° C. for 30minutes, the resulting solution was cooled to room temperature, andconcentrated. The residue was dissolved in chloroform, washed withwater, and then saturated brine, and dried over anhydrous sodiumsulfate. After filtration and concentration, reddish brown oil (19.52 g)was obtained. The product was purified by silica gel columnchromatography (Kieselgel 60=1.0 kg, chloroform/methanol=120/1) toobtain the compound ( 4!-(43)-592) (10.74 g) as a yellow solid.

Melting point: 128.0°-132.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 2.32 (s,3H), 3.40-3.85 (br, 8H), 7.70 (dd, 1H), 8.33 (d, 1H), 8.86 (d, 1H),10.39 (bs, 1H)

Example 43 Preparation of 4-acetamido-3-aminobenzoic acid morpholide (4!-(44)-592)

The compound ( 4!-(43)-592) (10.73 g) prepared in Example 42 wasdissolved in ethanol (400 ml). After the solution was heated on a bathat 60° C. for 30 minutes, hydrazine monohydrate (4 ml) and a suspensionof 10% Pd/C (0.55 g) in ethanol (2 ml) were added to the solution. Themixture was stirred at the same temperature for 30 minutes. Theinsolubles were filtered through celite, and the filtrate wasconcentrated to obtain a crude product (12.67 g). The product waspurified by silica gel column chromatography (Kieselgel 60=600 g,chloroform/methanol=10/1) to obtain the compound ( 4!-(44)-592) (4.63 g)as a light yellow solid.

Melting point: 198.0°-200.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 2.22 (s,3H), 3.35-3.85 (br, 8H), 3.88 (bs, 2H), 6.64 (dd, 1H), 6.71 (d, 1H),7.04 (d, 1H), 8.04 (bs, 1H)

Example 44 Preparation of 4-acetamide-3-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methylamino!benzoicacid morpholide ( 4!-(45)-592)

A solution of the compound ( 4!-(44)-592) (4.57 g) prepared in Example43, N-(triphenylmethyl)-5- 4'-(bromomethyl)biphenyl-2-yl!tetrazole(10.65 g), diisopropylethylamine (30.3 ml), and chloroform (270 ml) wasstirred in an oil bath at 70° C. for 4 hours under a nitrogen gasatmosphere. The reaction solution was cooled, and concentrated to obtaina yellow solid (19.45 g). The product was purified by silica gel columnchromatography (Kieselgel 60=700 g, chloroform/methanol=30/1) to obtainthe compound ( 4!-(45)-592) (6.55 g) as light yellow foam.

¹ H-NMR (500 MHz, CDCl₃) δ: 2.11 (s, 3H), 3.15-3.90 (br, 8H), 4.17 (d,2H), 4.42 (t, 1H), 6.58 (s, 1H), 6.63 (d, 1H), 6.95 (d, 6H), 7.07-7.13(m, 6H), 7.25-7.37 (m, 8H), 7.43-7.51 (m, 3H), 7.88 (d, 1H), 7.93 (s,1H)

Example 45 Preparation of 4-acetamido-3-N-2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methyl!valeramido!benzoicacid morpholide ( 4!-(46)-592')

The compound ( 4!-(45)-592) (5.80 g) prepared in Example 44 and4-dimethylaminopyridine (0.96 g) were dissolved in dry pyridine (58 ml),and valeryl chloride (2.8 ml) was added dropwise to the solution. Themixture was stirred at room temperature for 1 hour, poured into icewater, extracted with chloroform, and washed with water. The solutionwas washed with saturated brine, dried over sodium sulfate, filtered,and concentrated to obtain yellowish brown oil (7.76 g). The product waspurified by silica gel column chromatography (Kieselgel 60=600 g,chloroform/methanol=60/1) to obtain the compound ( 4!-(46)-592') (5.57g) as yellow foam.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.81 (t, 3H), 1.14-1.25 (m, 2H), 1.51-1.61(m, 2H), 1.76 (s, 3H), 1.86 (dr, 1H), 1.98 (dr, 1H), 3.25-4.00 (br, 8H),4.08 (d, 1H), 5.43 (d, 1H), 6.60 (s, 1H), 6.94 (d, 6H), 7.06-7.10 (m,4H), 7.21 (d, 1H), 7.25-7.35 (m, 10H), 7.45-7.53 (m, 2H), 7.92 (dd, 1H),8.12 (d, 1H)

Example 46 Preparation of 4-acetamido-3-N-2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!valeramido!benzoic acidmorpholide (Compound No. 592)

The compound ( 4!-(46)-592') (5.57 g) prepared in Example 45 wasdissolved in tetrahydrofuran (60 ml), and concentrated hydrochloric acid(60 ml) was added to the solution while cooling on ice. The solution wasallowed to stand at room temperature for 6 hours. The reaction solutionwas adjusted to approximately pH 7 with 10N NaOH aqueous solution andconcentrated. The residue was dissolved in chloroform, washed with waterand then saturated brine, dried over sodium sulfate, filtered, andconcentrated to obtain light yellow oil (3.95 g). The product waspurified by silica gel column chromatography (Kieselgel 60=270 g,chloroform/methanol=15/1) to obtain a light yellow solid (3.48 g). Theproduct was further added to acetone (30 ml), sonicated, and filtered.The filtrate was concentrated to obtain a solid (1.47 g). To the solid,1N NaOH aqueous solution (3.55 ml) was added, and the solution wasadjusted to pH 10. After water (60 ml) was added, the whole wassonicated, and filtered through celite. The filtrate was adjusted to pH4 with 1N HCl aqueous solution, and the precipitated solid was filteredout to obtain the above-captioned Compound No. 592 (0.86 g) as acolorless solid.

Melting point: 127.0°-131.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.84 (t,3H), 1.17-1.30, 1.54-1.64 (each m, each 2H), 1.95, 2.09 (each dt, each1H), 2.24 (s, 3H), 3.45-3.95 (br, 8H), 4.07, 5.56 (each d, each 1H),6.58 (bs, 1H), 6.85 (bd, 1H), 6.99, 7.03 (each d, each 2H), 7.36 (dd,1H), 7.40-7.60 (m, 2H), 7.46 (d, 1H), 7.87 (bd, 1H), 8.40 (bd, 1H),13.6-14.0 (br, 1H)

Example 47 Preparation of ethyl 4-dimethylamino-3-nitrobenzoate (5!-(52)-591)

Ethyl 4-dimethylaminobenzoate (9.10 g) was dissolved in sulfuric acid(14 ml), and mixed acid (concentrated sulfuric acid/concentrated nitricacid=1/1) (9.0 ml) was added dropwise at room temperature. The reactionsolution was stirred for 4 hours while maintaining at 5° C.-10° C. Thereaction solution was poured into ice water (100 g). The precipitatedcrystals were filtered, and washed with water. The resulting crystalswere recrystallized from water/methanol to obtain the above-captionedcompound ( 5!-(52)-591) (10.56 g) as yellow needle crystals.

Melting point: 78.5°-79.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 1.38 (t, 3H),2.99 (s, 6H), 4.35 (q, 2H), 6.97 (d, 1H), 8.01 (dd, 1H), 8.44 (d, 1H)

Example 48 Preparation of 4-dimethylamino-3-nitrobenzoic acid (5!-(53)-591)

A solution of the compound ( 5!-(52)-591) (10.0 g) prepared in Example47, tetrahydrofuran (250 ml), methanol (100 ml), and 1N NaOH aqueoussolution (100 ml) was stirred at room temperature for 18 hours.Tetrahydrofuran was evaporated under reduced pressure, and the residuewas adjusted to pH 4-5 with 1N HCl aqueous solution. The precipitatedcrystals were collected by filtration and dried to obtain theabove-captioned compound ( 5!-(53)-591) (8.76 g) as a yellow solid.

Melting point: 212.0°-215.5° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 2.93 (s,6H), 7.20 (d, 1H), 7.93 (dd, 1H), 8.24 (d, 1H), 12.84 (s, 1H)

Example 49 Preparation of 4-dimethylamino-3-nitrobenzoic acid morpholide( 5!-(54)-591)

The compound ( 5!-(53)-591) (8.00 g) prepared in Example 48 wasdissolved in dry tetrahydrofuran (200 ml), and 1-hydroxybenzotriazole(5.40 g) and dicyclohexylcarbodiimide (8.30 g) were added to thesolution. The mixture was stirred at room temperature for 30 minutes.Then morpholine (3.65 g) was added to the solution. The mixture wasstirred for 16 hours. The precipitated insolubles were filtered out, andthe filtrate was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (Kieselgel 60=180 g,chloroform) to obtain the above-captioned compound ( 5!-(54)-591) (10.43g) as a yellow solid.

Melting point: 89.5°-91.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 2.95 (s,6H), 3.5-3.8 (br, 8H), 7.01 (d, 1H), 7.50 (dd, 1H), 7.89 (d, 1H)

Example 50 Preparation of 3-amino-4-dimethylaminobenzoic acid morpholide( 5!-(55)-591)

With vigorously stirring, a solution of the compound ( 5!-(54)-591)(0.50 g) prepared in Example 49 in ethanol (50 ml) was heated on an oilbath at 50° C. To the solution, 10% Pd/C (0.050 g) wetted with ethanoland then hydrazine monohydrate (0.5 ml) were added successively. Afterstirring for 20 minutes, the catalyst was removed by filtration throughcelite, and the solution was concentrated. The residue was purified bysilica gel column chromatography (Kieselgel 60=15 g, hexane/ethylacetate=1/1) to obtain the above-captioned compound ( 5!-(55)-591) (0.40g) as a light red solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 2.68 (s, 6H), 3.4-3.8 (br, 8H), 6.73-6.76(m, 2H), 6.97 (d, 1H)

Example 51 Preparation of 4-dimethylamino-3-valeramidobenzoic acidmorpholide ( 5!-(56)-591)

The compound ( 5!-(55)-591) (0.58 g) prepared in Example 50 wasdissolved in anhydrous pyridine, and valeryl chloride (0.27 ml) wasadded to the solution. The mixture was stirred at room temperature for30 minutes. After water was added, the whole was extracted with ethylacetate. The extract was dried over anhydrous sodium sulfate, and thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (Kieselgel 60=20 g,chloroform/methanol=20/1) to obtain the above-captioned compound (5!-(56)-591) (0.69 g) as a light yellow solid.

Melting point: 92.5°-96.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.97 (t, 3H),1.38 (sext, 2H), 1.73 (quint, 2H), 2.42 (t, 2H), 2.64 (s, 6H), 3.4-3.9(br, 8H), 7.2-7.3 (m, 2H), 8.31 (s, 1H), 8.42 (s, 1H)

Example 52 Preparation of 4-dimethylamino-3-N- 2'-(1-triphenylmethyltetrazol-5-yl)biphenyl-4-yl!methyl!-valeramidobenzoicacid morpholide ( 5!-(57)-591')

The compound ( 5!-(56)-591) (0.05 g) prepared in Example 51 wasdissolved in dimethyl sulfoxide (10 ml), and powdered potassiumhydroxide (0.13 g) was added to the solution. The mixture was stirred atroom temperature for several minutes. After the powder of potassiumhydroxide was dissolved, N-(triphenylmethyl)-5-4'-(bromomethyl)biphenyl-2-yl!tetrazole (1.00 g) was added to thesolution. The mixture was stirred at room temperature for 1.5 hours. Asmall amount of water was added to the solution, and the whole wasextracted with ethyl acetate. The solution was washed with water, anddried over anhydrous sodium sulfate. The solvent was evaporated, and theresidue was purified by silica gel column chromatography (Kieselgel60=10 g, hexane/ethyl acetate=2/1) to obtain the above-captionedcompound ( 5!-(57)-591') (1.03 g) as colorless foam.

Melting point: 93.0°-94.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.85 (t, 3H),1.21 (sext, 2H), 1.63 (quint, 2H), 2.10 (dt, 1H), 2.26 (dt, 1H), 2.93(s, 6H), 3.1-3.9 (br, 8H), 4.01 (d, 1H), 5.60 (d, 1H), 6.59 (d, 1H),6.8-7.0 (m, 13H), 7.2-7.4 (m, 9H), 7.4-7.5 (m, 2H), 7.86 (d, 1H)

Example 53 Preparation of 4-dimethylamino-3-N- 2'-(1H-tetrazol-5-yl)biphenyl-4-yl!methyl!valeramidobenzoic acid morpholide( 5!-(57)-591) (Compound No. 591)

The compound ( 5!-(57)-591') (0.15 g) prepared in Example 52 wasdissolved in tetrahydrofuran (3 ml), and 12% HCl aqueous solution (0.45ml) was added to the solution. The mixture was stirred for 24 hours.After the mixture was adjusted to pH 11 by adding 1N NaOH aqueoussolution, tetrahydrofuran in the solvent was evaporated, and solids wereremoved by filtration. To the mother liquid, 1N HCl aqueous solution wasadded dropwise, and the solvent was adjusted to pH 4-5, and theprecipitated solid was collected by filtration. The residue was purifiedby silica gel column chromatography (Kieselgel 60=5 g, chloroform/ethylacetate=10/1) to obtain the above-captioned compound ( 5!-(57)-591)(0.080 g) as white foam.

Melting point: 102.0°-105.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 0.82 (t,3H), 1.2-1.3 (m, 2H), 1.5-1.6 (m, 2H), 2.10 (dt, 1H), 2.35 (dt, 1H),2.87 (s, 6H), 3.2-3.7 (br, 8H), 4.22 (d, 1H), 5.48 (d, 1H), 6.89 (d,1H), 7.02 (d, 2H), 7.1-7.2 (m, 5H), 7.31 (dd, 1H), 7.53 (d, 1H), 7.7-7.8(m, 2H)

Example 54 Preparation of 4-dimethylamino-3-N-(4-methoxycarbonylphenyl)methyl!valeramido!benzoic acid morpholide (5!-(57)-158')

After 60% NaH (0.72 g) was washed with n-hexane, dry DMSO (46 ml) waspoured thereto, and the mixture was stirred at room temperature for 15minutes. To the resulting suspension, a solution of the compound (5!-(56)-591) (4.63 g) prepared in Example 51 in dry DMSO (46 ml) wasadded dropwise at room temperature over 10 minutes with stirring. Thereaction system which had been cloudy became yellowish orange suspensionand foamed. Then methyl 4-bromomethylbenzoate (3.83 g) was added over 2minutes, and the reaction system was stirred at room temperature for 3hours, whereby the reaction system became clear yellowish orangesolution. The reaction solution was poured into 1N HCl aqueous solution,extracted with ethyl acetate, washed with water and saturated brine,dried over anhydrous sodium sulfate, and concentrated to obtain a lightyellow solid (6.76 g). The solid was purified by silica gel columnchromatography (Kieselgel 60=670 g, chloroform/acetone=15/1) to obtainthe above-captioned compound ( 5!-(57)-184') (6.71 g) as a light yellowsolid.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.85 (t, 3H), 1.2-1.3 (m, 2H), 1.5-1.6 (m,2H), 2.10 (dt, 1H), 2.35 (dt, 1H), 2.87 (s, 6H), 3.2-3.7 (br, 8H), 4.22(d, 1H), 5.48 (d, 1H), 6.89 (d, 1H), 7.02 (d, 2H), 7.1-7.2 (m, 5H), 7.31(dd, 1H), 7.53 (d, 1H), 7.7-7.8 (m, 2H)

Example 55 Preparation of 3-N-(4-carboxyphenyl)methyl!valeramido!-4-dimethylaminobenzoic acidmorpholide ( 5!-(57)-184) (Compound No. 184)

The compound ( 5!-(57)-184') (6.71 g) prepared in Example 53 wasdissolved in a solution of methanol (67 ml) and tetrahydrofuran (67 ml).Then 1N NaOH aqueous solution (67 ml) was added thereto, and the mixturewas allowed to stand for 14 hours. The reaction solution wasneutralized, concentrated, adjusted to approximately pH 1, extractedwith chloroform, washed with water, dried over anhydrous sodium sulfate,and concentrated to obtain white foam (5.63 g). The white foam waspurified by silica gel column chromatography (Kieselgel 60=280 g,chloroform/methanol=15/1) to obtain white foam (5.63 g). Further,n-hexane was added to the resulting foam, and the product wascrystallized, and dried under vacuum to obtain the above-captionedcompound ( 5!-(57)-184) (4.45 g) as white crystals.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.85 (t, 3H), 1.2-1.3 (m, 2H), 1.5-1.6 (m,2H), 2.10 (dt, 1H), 2.35 (dt, 1H), 2.87 (s, 6H), 3.2-3.7 (br, 8H), 4.22(d, 1H), 5.48 (d, 1H), 6.89 (d, 1H), 7.02 (d, 2H), 7.1-7.2 (m, 5H), 7.31(dd, 1H), 7.53 (d, 1H), 7.7-7.8 (m, 2H)

Example 56 Preparation of methyl 3-valeramidobenzoate ( 6!-(62)-90)

To anhydrous pyridine (120 ml), methyl 3-aminobenzoate (5.00 g) wasdissolved, and valeryl chloride (4.13 ml) was added while cooling onice. The mixture was stirred at room temperature for 4 hours. Distilledwater was added to the solution. The whole was extracted with ethylacetate, washed with 5% sodium hydrogencarbonate aqueous solution andwater, and dried over anhydrous sodium sulfate. The solvent wasevaporated, and the residue was purified by silica gel columnchromatography (Kieselgel 60=170 g, hexane/ethyl acetate=3/1) to obtainthe above-captioned compound ( 6!-(62)-90) (7.70 g) as a white solid.

Melting point: 97.0°-98.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.95 (t, 3H),1.40 (sext, 2H), 1.72 (quint, 2H), 2.38 (t, 2H), 3.91 (s, 3H), 7.30-7.40(br, 1H), 7.39 (t, 1H), 7.77 (d, 1H), 7.91 (d, 1H), 8.03 (s, 1H)

Example 57 Preparation of 3-valeramidobenzoic acid ( 6!-(63)-90)

The compound ( 6!-(62)-90) (7.56 g) prepared in Example 56 was dissolvedin tetrahydrofuran (180 ml) and methanol (80 ml). To the solution, 1NNaOH aqueous solution (80 ml) was added. The mixture was stirred at roomtemperature for 5 hours. The solution was concentrated, and the organicsolvents were evaporated. The residue was adjusted to pH 2 by adding 1NHCl aqueous solution. The precipitated crystals were collected byfiltration, washed with distilled water, and dried to obtain theabove-captioned compound ( 6!-(63)-90) (6.43 g) as white crystals.

Melting point: 210.5°-212.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 0.88 (t,3H), 1.33 (sext, 2H), 1.58 (quint, 2H), 2.32 (t, 2H), 7.41 (t, 1H), 7.60(d, 1H), 7.82 (d, 1H), 8.23 (s, 1H), 10.04 (s, 1H), 12.91 (s, 1H)

Example 58 Preparation of 3-valeramidobenzoic acid morpholide (6!-(64)-90)

The compound ( 6!-(63)-90) (6.30 g) prepared in Example 57 was dissolvedin tetrahydrofuran (126 ml). To the solution, dicyclohexylcarbodiimide(71.7 g) and 1-hydroxybenzotriazole (4.04 g) were added. The mixture wasstirred at room temperature for 5 minutes. After morpholine (3.28 g) wasadded, the mixture was stirred at room temperature for 21 hours. Theinsolubles were filtered out, and the filtrate was concentrated. Theresidue was purified by silica gel column chromatography (Kieselgel60=230 g, chloroform/methanol=20/1) to obtain the above-captionedcompound ( 6!-(64)-90) (8.09 g) as colorless oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.95 (t, 3H), 1.38 (sext, 2H), 1.68 (quint,2H), 2.33 (t, 2H), 3.3-3.9 (br, 8H), 7.07 (d, 1H), 7.31 (t, 1H), 7.57(s, 1H), 7.58 (d, 1H), 8.01 (s, 1H)

Example 59 Preparation of 3-N-(4-methoxycarbonylphenyl)methyl!valeramidobenzoic acid morpholide (6!-(65)-90') (Compound No. 612)

To dry dimethyl sulfoxide (80 ml), 60% NaH (2.05 g) was added to thesolution. The mixture was stirred at room temperature for 15 minutes. Asolution of the compound ( 6!-(64)-90) (7.96 g) prepared in Example 58in dry dimethyl sulfoxide (80 ml) was added dropwise, and then methyl4-bromomethylbenzoate (7.56 g) was added. The mixture was stirred atroom temperature for 1 hour. The solution was poured into 1N HCl aqueoussolution (200 g) cooled with ice, extracted with ethyl acetate, washedwith water and saturated brine, dried over anhydrous sodium sulfate, andconcentrated. The residue was purified by silica gel columnchromatography (Kieselgel 60=300 g, hexane/ethyl acetate=1/3) to obtainthe above-captioned compound ( 6!-(65)-90') (Compound No. 612) (7.27 g)as white foam.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.82 (t, 3H), 1.22 (sext, 2H), 1.59 (quint,2H), 2.06 (t, 2H), 3.0-3.8 (br, 8H), 3.94 (s, 3H), 4.95 (s, 2H), 6.94(s, 1H), 7.10 (d, 1H), 7.25 (d, 2H), 7.37 (d, 1H), 7.42 (t, 1H), 8.00(d, 1H)

Example 60 Preparation of 3- N-(4-carboxyphenyl)methyl!valeramidobenzoicacid morpholide ( 6!-(65)-90) (Compound No. 90)

The compound ( 6!-(65)-90') (5.95 g) prepared in Example 59 wasdissolved in methanol (60 ml) and tetrahydrofuran (60 ml). 1N NaOHaqueous solution (60 ml) was added thereto, and the mixture was stirredat room temperature overnight. The organic solvents were evaporatedunder reduced pressure. The residue was adjusted to pH 2 by adding 1NHCl aqueous solution, and extracted with ethyl acetate, and dried overanhydrous sodium sulfate. The solvent was evaporated, and the residuewas purified by silica gel column chromatography (Kieselgel 60=160 g,chloroform/methanol=10/1) to obtain the above-captioned compound (6!-(65)-90) (Compound No. 90) (3.77 g) as a white solid.

Melting point: 169.5°-173.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.82 (t,3H), 1.22 (sext, 2H), 1.59 (quint, 2H), 2.09 (t, 2H), 3.0-3.8 (br, 8H),4.97 (s, 2H), 6.98 (s, 1H), 7.11 (d, 1H), 7.27 (d, 2H), 7.40 (d, 1H),7.45 (t, 1H), 8.06 (d, 1H)

Example 61 Preparation of 4-hexyl-4-nitrobenzoic acid ( 5!-(53)-75)

In concentrated sulfuric acid (20 ml), 4-hexylbenzoic acid (7.50 g) wasdissolved while cooling on ice. Mixed acid of concentrated sulfuricacid/concentrated nitric acid (1/1) (7.0 ml) was added thereto dropwiseover 5 minutes. The mixture was stirred for 20 minutes while cooling onice and further for 30 minutes at room temperature. After the reactionwas completed, the solution was poured into ice water. The precipitatedcrystals were collected by filtration, and dissolved in ethyl acetate.The solution was washed with water, and the organic layer was dried overanhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was recrystallized from cyclohexane to obtainthe above-captioned compound ( 5!-(53)-75) (7.60 g) as colorless needlecrystals.

Melting point: 106.5°-107.5° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.96 (t,3H), 1.2-1.5 (m, 4H), 1.39 (bquint, 2H), 1.65 (bquint, 2H), 2.82 (t,2H), 7.48 (d, 1H), 8.21 (dd, 1H), 8.58 (d, 1H)

Example 62 Preparation of 4-hexyl-3-nitrobenzoic acid morpholide (5!-(54)-75)

The compound ( 5!-(53)-75) (7.60 g) prepared in Example 61 was dissolvedin anhydrous chloroform (152 ml). Then,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.37 g),1-hydroxybenzotriazole (4.48 g), and morpholine (6.31 g) were added tothe solution. The reaction mixture was stirred at room temperature for 7hours. After the reaction was completed, chloroform was added. Thesolution was washed with 0.5N HCl aqueous solution, 0.5N NaOH aqueoussolution, and distilled water. After the organic layer was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (Kieselgel 60=150 g, hexane/ethyl acetate=1/1) to obtainthe above-captioned compound ( 5!-(54)-75) (8.50 g) as a white solid.

Melting point: 68.5°-71.5° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.93 (t, 3H),1.2-1.4 (m, 4H), 1.39 (bquint, 2H), 1.62 (bquint, 2H), 2.90 (t, 2H),3.3-4.1 (br, 8H), 7.41 (d, 1H), 7.57 (dd, 1H), 7.92 (d, 1H)

Example 63 Preparation of 3-amino-4-hexylbenzoic acid morpholide (5!-(55)-75)

The compound ( 5!-(54)-75) (700 mg) prepared in Example 62 was dissolvedin ethanol (35 ml). After the solution was heated to 50° C., asuspension of 10% Pd/C (70 mg) in ethanol was added, and hydrazinemonohydrate (0.35 ml) was added to the solution. The solution wasstirred at 50° C. for 30 minutes. After the reaction was completed, thesolution was filtered through celite 545 to remove the catalyst. Thesolvent was evaporated under reduced pressure. The residue was purifiedby silica gel column chromatography (Kieselgel 60=20 g, ethyl acetate)to obtain the above-captioned compound ( 5!-(55)-75) (631 mg) ascolorless oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.82 (t, 3H), 1.1-1.3 (m, 4H), 1.29 (bquint,2H), 1.53 (bquint, 2H), 2.41 (t, 2H), 3.3-3.9 (br, 10H), 6.64 (d, 1H),6.96 (d, 1H), 7.20 (s, 1H)

Example 64 Preparation of 4-hexyl-3-(4-methoxycarbonylphenyl)methyl!aminobenzoic acid morpholide (5!-(57)-75')

The compound ( 5!-(55)-75) (600 mg) prepared in Example 63 was dissolvedin acetic acid (6.0 ml). Then, 4-methoxycarbonylbenzaldehyde (373 mg)was added. The mixture was stirred at room temperature for 4 hours.Then, boranediethylamine complex (146 mg) was added to the solution. Themixture was stirred at room temperature for 30 minutes. After thereaction was completed, water was added to the solution. The solutionwas extracted with ethyl acetate, washed with distilled water, and driedover anhydrous sodium sulfate. The solvent was evaporated under reducedpressure, and the residue was purified by silica gel columnchromatography (Kieselgel 60=30 g, hexane/ethyl acetate=1/1) to obtainthe above-captioned compound ( 5!-(57)-75') (841 mg) as a white solid.

Melting point: 89.0°-90.5° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.82 (t, 3H),1.2-1.3 (m, 4H), 1.31 (bquint, 2H), 1.57 (bquint, 2H), 2.45 (t, 2H),3.0-3.8 (br, 8H), 3.84 (s, 3H), 4.14 (bs, 1H), 4.40 (s, 2H), 6.41 (d,1H), 6.65 (dd, 1H), 7.01 (d, 1H), 7.34 (d, 1H), 7.93 (d, 1H)

Example 65 Preparation of 3-(4-carboxyphenyl)methyl!amino-4-hexylbenzoic acid morpholide (5!-(57)-75) (Compound No. 75)

The compound ( 5!-(57)-75') (46 mg) prepared in Example 64 was dissolvedin tetrahydrofuran (1.0 ml) and methanol (0.5 ml). Then, 1N NaOH aqueoussolution (0.25 ml) was added to the solution. The mixture was stirred atroom temperature for 24 hours. After the reaction was completed, thesolution was adjusted to approximately pH 5 with 1N HCl aqueoussolution, and extracted with ethyl acetate. The solution was dried overanhydrous sodium sulfate, and the solvent was evaporated under reducedpressure. The residue was purified by preparative thin layerchromatography (Merck 13792, chloroform/methanol=10/1) to obtain theabove-captioned compound ( 5!-(57)-75) (Compound No. 75) (39.8 mg) as alight yellow solid.

Melting point: 205.0°-209.5° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.82 (t,3H), 1.2-1.3 (m, 4H), 1.32 (bquint, 2H), 1.58 (quint, 2H), 2.45 (t, 2H),3.0-4.9 (br, 8H), 4.26 (s, 2H), 6.43 (d, 1H), 6.65 (dd, 2H), 7.01 (d,1H), 7.36 (d, 2H), 7.98 (d, 2H)

Example 66 Preparation of 4-isopropyl-3-nitrobenzoic acid ( 5!-(53)-372)

Cuminic acid (5.0201 g) was suspended in concentrated sulfuric acid (7.5ml), and a solution of concentrated sulfuric acid/70% nitric acid (1/1,v/v) (5.0 ml) was added thereto dropwise under stirring while cooling onice. After nearly white suspension was stirred at room temperature for 1hour, the suspension was poured into ice water. The resulting lightyellow crystals were collected by filtration, washed with water, anddried by vacuum heating (60° C.) to obtain the above-captioned compound( 5!-(53)-372) (6.0717 g).

Melting point: 152.0°-155.5° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 1.28 (d,6H), 3.28 (sept, 1H), 7.79 (d, 1H), 8.16 (dd, 1H), 8.24 (d, 1H), 13.47(b, 1H)

Example 67 Preparation of 4-isopropyl-3-nitrobenzoic acid morpholide (5!-(54)-372)

The compound ( 5!-(53)-372) (5.9731 g) prepared in Example 66 wasdissolved in anhydrous dimethylformamide (DMF) (90 ml). Then,1-hydroxybenzotriazole (5.0157 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (7.1155 g),triethylamine (5.2 ml), and morpholine (3.2 ml) were added to thesolution. The mixture was stirred at room temperature for 16 hours. Asmall amount of water was added to the resulting yellowish orangesolution including the white salt to obtain a homogeneous solution. Thesolution was concentrated, and the residue was dissolved in chloroform.To precipitate the solid, 1N HCl aqueous solution was added. After theprecipitated solid was collected by filtration and washed withchloroform, the filtrate and the washing were washed with 1N HCl aqueoussolution and saturated brine. The washed product was dried overanhydrous sodium sulfate, and concentrated to obtain yellowish brown oil(8.7070 g). The oil was purified by silica gel column chromatography(Kieselgel 60=260 g, hexane/ethyl acetate=2/1) to obtain theabove-captioned compound ( 5!-(54)-372) (7.7001 g) as light yellow oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 1.97 (d, 6H), 3.43 (sept, 1H), 3.72 (b, 8H),7.55 (d, 1H), 7.60 (dd, 1H), 7.76 (d, 1H)

Example 68 Preparation of 3-amino-4-isopropylbenzoic acid morpholide (5!-(55)-372)

The compound ( 5!-(54)-372) (0.4050 g) prepared in Example 67 wasdissolved in ethanol (20 ml). Then, a suspension of 10% Pd/C (0.0405 g)in ethanol (4 ml), and hydrazine monohydrate (0.4 ml) were added to thesolution. The mixture was stirred in an oil bath at 60° C. for 20minutes. After the reaction was completed, the solution was filteredthrough a glass filter carrying celite 545 thereon to remove thecatalyst. The filtrate was concentrated to obtain colorless oil (0.3912g). The crude oil was purified by silica gel column chromatography(Kieselgel 60=20 g, ethyl acetate) to obtain the above-captionedcompound ( 5!-(55)-372) (0.3580 g) as white crystals.

Melting point: 112.0°-115.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 1.25 (d,6H), 2.89 (sept, 1H), 3.4-3.9 (b, 10H), 6.72 (d, 1H), 6.76 (dd, 1H),7.14 (d, 1H)

Example 69 Preparation of 4-isopropyl-3-valeramidobenzoic acidmorpholide ( 5!-(56)-372)

The compound ( 5!-(55)-372) (0.4148 g) prepared in Example 68 wasdissolved in anhydrous pyridine (5.0 ml). Then, valeryl chloride (0.2ml) was added thereto dropwise while cooling on ice with stirring. Afterthe reaction solution was stirred on ice for 3 hours, the reactionsolution was poured into ice water. The solution was extracted withethyl acetate, washed with water and saturated brine, dried overanhydrous sodium sulfate, and concentrated. The resulting light yellowoil (0.6027 g) was purified by silica gel column chromatography(LiChroprep Si 60=30 g, chloroform/acetone=7/1) to obtain theabove-captioned compound ( 5!-(56)-372) (0.4903 g) as light yellow oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.97 (t, 3H), 1.23 (d, 6H), 1.43 (sext, 2H),1.73 (quint, 2H), 2.40 (t, 2H), 3.01 (sept, 1H), 3.45-3.9 (b, 8H), 7.23(d, 1H), 7.30 (d, 1H), 7.33 (bs, 1H), 7.65 (s, 1H)

Example 70 Preparation of 4-isopropyl-3-N-(4-methoxycarbonylphenyl)methyl!valeramido!benzoic acid morpholide (5!-(57)-372')

After oil of 60% NaH (0.0729 g) was removed by washing with hexane,anhydrous dimethyl sulfoxide (DMSO) (4.6 ml) was added to the washedNaH. The mixture was stirred at room temperature for 30 minutes. Asolution of the compound ( 5!-(56)-372) (0.4659 g) prepared in Example69 in anhydrous DMSO (4.6 ml) was added dropwise at room temperature toobtain a reddish brown suspension. To the suspension, a solution ofmethyl 4-(bromomethyl)benzoate (0.3853 g) in anhydrous DMSO (2.3 ml) wasadded dropwise. After the resulting reddish brown solution was stirredat room temperature for 3.5 hours, the reaction solution was poured intocold 1N HCl aqueous solution. The solution was extracted withchloroform. The chloroform layer was washed with water and saturatedbrine, dried over anhydrous sodium sulfate, and concentrated to obtainreddish brown oil (0.8369 g). The crude oil was purified by silica gelcolumn chromatography (LiChroprep Si 60=42 g, Chloroform/acetone=20/1)to obtain the above-captioned compound ( 5!-(57)-372') (0.4073 g) aslight yellow crystals.

Melting point: 105.0°-108.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.83 (t,2H), 1.18 (d, 3H), 1.17-1.25 (m, 2H), 1.21 (d, 3H), 1.53-1.65 (m, 2H),1.89 (dt, 1H), 2.01 (dt, 1H), 3.03 (sept, 1H), 3.25-3.9 (b, 8H), 3.91(s, 3H), 4.00 (d, 1H), 5.71 (d, 1H), 6.59 (d, 1H), 7.27 (d, 2H), 7.43(dd, 1H), 7.46 (d, 1H), 7.93 (d, 2H)

Example 71 Preparation of 3-N-(4-carboxyphenyl)methyl!valeramido!-4-isopropylbenzoic acid morpholide (5!-(57)-372) (Compound No. 372)

The compound ( 5!-(57)-372') (0.3812 g) prepared in Example 70 wasdissolved in a solvent of methanol (3.8 ml) and tetrahydrofuran (3.8ml). Then, 1N NaOH aqueous solution (3.8 ml) was added to the solution,and the reaction solution was allowed to stand at room temperature for13 hours. After the reaction solution was neutralized with 1N HClaqueous solution, the solution was concentrated. The residue wasacidified with 1N HCl aqueous solution, and extracted with chloroform.The chloroform layer was washed with water and saturated brine, driedover anhydrous sodium sulfate, and concentrated to obtain yellow oil(0.3645 g). The crude oil was purified by silica gel columnchromatography (Kieselgel 60=20 g, chloroform/methanol=15/1) to obtainthe above-captioned compound ( 5!-(57)-372) (Compound No. 372) (0.2548g) as white crystals.

Melting point: 224.0°-227.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.83 (t,3H), 1.19 (d, 3H), 1.18-1.30 (m, 2H), 1.21 (d, 3H), 1.59 (tt, 2H), 1.92(dt, 1H), 1.97 (dr, 1H), 3.05 (sept, 1H), 2.85-3.9 (b, 8H), 4.02 (d,1H), 5.73 (d, 1H), 6.62 (s, 1H), 7.30 (d, 2H), 7.44 (d, 1H), 7.45 (s,1H), 7.47 (d, 1H), 7.98 (d, 2H)

Example 72 Preparation of 4-methyl-3-nitrobenzoic acid ( 5!-(53)-278)

In concentrated sulfuric acid (15.1 ml), p-toluic acid (10.094 g) wassuspended. While the temperature of the solution was maintained at lessthan 30° C., a solution of a mixture of concentrated sulfuric acid/70%nitric acid (1/1, v/v) (10.1 ml) was added dropwise under stirring whilecooling on ice. After the light yellow suspension was stirred at roomtemperature for 1.5 hours, the suspension was poured into ice water. Theresulting light yellow crystals were collected by filtration, washedwith water, and dried by vacuum heating (60° C.) to obtain theabove-captioned compound ( 5!-(53)-278) (12.755 g).

Melting point: 188.0°-190.5° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 2.59 (s,3H), 7.65 (d, 1H), 8.13 (dd, 1H), 8.42 (d, 1H), 13.49 (b, 1H)

Example 73 Preparation of 4-methyl-3-nitrobenzoic acid morpholide (5!-(54)-278)

The compound ( 5!-(53)-278) (6.5272 g) prepared in Example 72 wasdissolved in anhydrous DMF (98 ml). Then, 1-hydroxybenzotriazole (6.3297g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (8.9795g), triethylamine (6.5 ml), and morpholine (4.1 ml) were added to thesolution. The mixture was stirred at room temperature for 4 hours. Asmall amount of water was added to the resulting yellowish orangesolution including the white salt to obtain a homogeneous solution. Thesolution was concentrated. The residue was dissolved in chloroform, andthe solution was washed with 1N HCl aqueous solution and saturatedbrine. The organic layer was dried over anhydrous sodium sulfate, andconcentrated to obtain yellowish brown crystals (8.9903 g). The productwas recrystallized from n-hexane/ethyl acetate to obtain theabove-captioned compound ( 5!-(54)-278) (7.8455 g) as light yellowcrystals.

Melting point: 108.0°-110.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 2.64 (s,3H), 3.35-4.0 (b, 8H), 7.42 (d, 1H), 7.57 (dd, 1H), 8.03 (d, 1H)

Example 74 Preparation of 3-amino-4-methylbenzoic acid morpholide (5!-(55)-278)

The nitro compound ( 5!-(54)-278) (1.208 g) prepared in Example 73 wasdissolved in ethanol (50 ml), and the solution was heated in an oil bathat 60° C. A suspension of 10% Pd/C (150 mg) in ethanol (3 ml) was addedto the solution, and hydrazine monohydrate (1 ml) was further added.After the mixture was heated for 15 minutes, the catalyst was filteredout through celite 545. The filtrate was concentrated. The residue waswashed with chloroform (100 ml)/water (20 ml), and concentrated toobtain the above-captioned compound ( 5!-(55)-278) (1.069 g) as lightyellow oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 2.17 (s, 3H), 3.4-4.9 (b, 10H), 6.69 (dd,1H), 6.71 (d, 1H), 7.05 (d, 1H)

Example 75 Preparation of 4-methyl-3-valeramidobenzoic acid morpholide (5!-(56)-278)

The aniline compound ( 5!-(55)-278) (1.07 g) prepared in Example 74 wasdissolved in anhydrous pyridine (20 ml), and the solution was cooled onice. Valeryl chloride (0.60 ml) was added dropwise to the solution, andthe solution was stirred on ice for 1 hour and further stirred at roomtemperature for 1.5 hours. The reaction solution was acidified with HCl,extracted with ethyl acetate, and concentrated. The crude product waspurified by silica gel column chromatography (Kieselgel 60=80 g, ethylacetate) to obtain the above-captioned compound ( 5!-(56)-278) (1.32 g)as colorless clear oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.97 (t, 3H), 1.39-1.46 (m, 2H), 1.72(quint, 2H), 2.26 (s, 3H), 2.39 (t, 2H), 3.4-4.9 (b, 8H), 7.10 (d, 1H),7.17 (d, 1H), 7.44 (bs, 1H), 7.71 (s, 1H)

Example 76 Preparation of 4-methyl-3-N-4-(methoxycarbonylphenyl)methyl!valeramido!benzoic acid morpholide (5!-(57)-278')

In anhydrous DMSO (5 ml), 50% NaH (140 mg) was suspended. A solution ofthe amide compound ( 5!-(56)-278) (553 mg) prepared in Example 75 inDMSO (6 ml) was added dropwise to the suspension. After the resultingdark red suspension was stirred for 25 minutes, methyl4-bromomethylbenzoate (458 mg) was added, and further the whole wasstirred for 3 hours. The reaction solution was poured into water,extracted with chloroform, and concentrated. The crude product waspurified by silica gel column chromatography (LiChroprep Si 60=80 g,ethyl acetate/hexane=2/1) to obtain the above-captioned compound (5!-(57)-278') (533 mg) as a white solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.82 (t, 3H), 1.17-1.23 (m, 2H), 1.54-1.60(m, 2H), 1.88 (dr, 1H), 1.94 (dr, 1H), 2.16 (s, 3H), 2.80-3.85 (b, 8H),3.91 (s, 3H), 4.19 (d, 1H), 5.51 (d, 1H), 6.70 (s, 1H), 7.27 (d, 2H),7.35 (s, 2H), 7.93 (d, 2H)

Example 77 Preparation of 4-methyl-3-N-4-(carboxyphenyl)methyl!valeramido!benzoic acid morpholide (5!-(57)-278) (Compound No. 278)

The ester compound ( 5!-(57)-278') (300 mg) prepared in Example 76 wasdissolved in a solvent of a mixture of methanol/THF (1/1) (10 ml). Then,1N NaOH aqueous solution (1.5 ml) was added to the solution. The mixturewas allowed to stand for 17 hours. The reaction solution was adjusted topH 4 with 1N HCl, and concentrated. The crude product was purified bysilica gel column chromatography (Kieselgel 60=25 g,chloroform/methanol=15/1) to obtain the above-captioned compound (5!-(57)-278) (compound No. 278) (215 mg) as a white solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.82 (t, 3H), 1.20-1.25 (m, 2H), 1.58(quint), 1.89 (dt, 1H), 2.00 (dt, 1H), 2.18 (s, 3H), 2.80-3.25 (b, 2H),3.35-3.85 (b, 6H), 4.18 (d, 1H), 5.55 (d, 1H), 6.71 (s, 1H), 7.34 (d,2H), 7.36 (s, 2H), 7.97 (d, 2H)

Example 78 Preparation of 4-dimethylamino-3-N-4-(1-triphenylmethyl-1H-tetrazol-5-yl)phenylmethyl!valeramido!benzoicacid morpholide ( 5!-(57)-604')

After oil of 60% NaH (0.3764 g) was removed by washing with hexane,anhydrous dimethyl sulfoxide (DMSO ) (15.7 ml) was added to thesolution. The mixture was stirred at room temperature for 30 minutes. Asolution of the compound ( 5!-(56)-591) (1.9608 g) prepared in Example51 in anhydrous DMSO (15.7 ml) was added dropwise at room temperature toobtain a light yellow solution. To the solution, a solution of5-(4-bromomethylphenyl)-1H-(N-triphenylmethyl)tetrazole (4.2463 g) inanhydrous DMSO (21.2 ml) was added dropwise. After the resulting whitesuspension was stirred at room temperature for 2 hours to obtain ayellowish brown solution, the reaction solution was poured into water.Saturated brine was added to the mixture, and the whole was extractedwith ethyl acetate. The ethyl acetate layer was washed with saturatedbrine, dried over anhydrous sodium sulfate, and concentrated to obtainyellowish brown oil (5.9581 g). The crude oil was purified by silica gelcolumn chromatography (Kieselgel 60=280 g, chloroform/acetone=20/1) toobtain the above-captioned compound ( 5!-(57)-604') (4.2329 g) as lightyellow foam.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.85 (t, 3H), 1.24 (sext, 2H), 1.63 (quint,2H), 2.10 (dr, 1H), 2.27 (dr, 1H), 2.88 (s, 6H), 2.95-3.85 (b, 8H), 4.14(d, 1H), 5.77 (d, 1H), 6.51 (s, 1H), 7.00 (d, 1H), 7.13-7.37 (m, 18H),7.95 (d, 2H)

Example 79 Preparation of 4-dimethylamino-3-N-4-(1H-tetrazol-5-yl)phenylmethyl!valeramido!benzoic acid morpholide (5!-(57)-604) (Compound No. 604)

The compound ( 5!-(57)-604') (4.1872 g) prepared in Example 78 wasdissolved in tetrahydrofuran (63 ml), and 12% HCl (31 ml) was addedthereto. The solution was allowed to stand at room temperature for 2hours. To the reaction solution, 20% NaOH aqueous solution was added,and the product was extracted as sodium salt, and washed with diethylether. The aqueous layer was adjusted to pH 4 with concentratedhydrochloric acid, and extracted with chloroform. The chloroform layerwas washed with saturated brine, dried over anhydrous sodium sulfate,and concentrated to obtain yellow foam (2.6963 g). The crude foam waspurified by silica gel column chromatography (kieselgel 60=150 g,chloroform/methanol=5/1) to obtain the above-captioned compound (5!-(57)-604) (Compound No. 604) (2.6132 g) as light yellow foam.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.79 (t, 3H), 1.22 (tq, 2H), 1.63 (quint,2H), 2.23 (dr, 1H), 2.31 (dt, 1H), 2.92 (s, 6H), 3.0-3.85 (b, 8H), 4.21(d, 1H), 5.72 (d, 1H), 6.69 (s, 1H), 7.05 (d, 1H), 7.29 (d, 2H), 7.37(d, 1H), 8.00 (d, 2H)

Example 80 Preparation of 3-n-amylamino-4-dimethylaminobenzoic acidmorpholide ( 7!-(71)-252)

The compound ( 5!-(55)-591) (50 mg) prepared in Example 50 was dissolvedin ethanol (1 ml), and 5% Pd/C (5 mg) was added thereto. Under ahydrogen gas atmosphere, valeraldehyde (0.03 ml) was added to themixture, and the mixture was stirred at room temperature for 1 hour.After the reaction was completed, the catalyst was removed by filtrationthrough celite, and solution was concentrated. The residue was purifiedby preparative thin layer chromatography (Merck 13872, hexane/ethylacetate=1/2) to obtain the above-captioned compound ( 7!-(71)-252) (39mg) as colorless oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.92 (t, 3H), 1.3-1.4 (m, 4H), 1.67 (quint,2H), 2.67 (s, 6H), 3.10 (t, 2H), 3.4-3.9 (br, 8H), 4.59 (br, 1H), 6.61(s, 1H), 6.70 (d, 1H), 6.96 (d, 1H)

Example 81 Preparation of -4-dimethylamino-3-N-(4-methoxycarbonylphenyl)methyl!-n-amylaminobenzoic acid morpholide (7!-(72)-252')

The compound ( 7!-(71)-252) (107 mg) prepared in Example 80 wasdissolved in chloroform (2.5 ml). Then, methyl 4-(bromomethyl)benzoate(154 mg) and diisopropylethylamine (432 mg) were added to the solution.The mixture was heated under reflux for 3 days. After the reaction wascompleted, the solution was concentrated, and the residue was purifiedby silica gel column chromatography (Kieselgel 60=7 g, ethylacetate/hexane=1/2) to obtain the above-captioned compound (7!-(72)-252') (134 mg) as colorless oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.84 (t, 3H), 1.1-1.3 (m, 4H), 1.48 (quint,2H), 2.93 (s, 6H), 3.07 (t, 2H), 3.2-3.8 (br, 8H), 4.41 (d, 2H), 6.74(d, 1H), 6.93 (d, 1H), 7.02 (dd, 1H), 7.13 (d, 2H), 7.88 (d, 2H)

Example 82 Preparation of 4-dimethylamino-3-N-(4-carboxyphenyl)methyl!-n-amylaminobenzoic acid morpholide (7!-(72)-252) (Compound No. 252)

The compound ( 7!-(72)-252') (125 mg) prepared in Example 81 wasdissolved in methanol (3 ml), and then 1N NaOH aqueous solution (1 ml)was added to the solution. The mixture was stirred at room temperaturefor 5.5 hours. After the reaction was completed, the solution wasadjusted to approximately pH 5 with 1N-HCl aqueous solution, andextracted with ethyl acetate. After the solution was dried overanhydrous sodium sulfate, the solvent was evaporated under reducedpressure. The residue was purified by silica gel column chromatography(Kieselgel 60=5 g, chloroform/methanol=10/1) to obtain theabove-captioned compound ( 7!-(72)-252) (Compound No. 252) (110 mg) aslight yellow foam.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.84 (t, 3H), 1.2-1.3 (m, 4H), 1.49 (quint,2H), 2.89 (s, 6H), 3.03 (t, 2H), 3.2-3.8 (br, 8H), 4.42 (d, 2H), 6.77(s, 1H), 6.92 (d, 1H), 7.03 (d, 1H), 7.14 (d, 2H), 7.93 (d, 2H)

Example 83 Preparation of 3-nitrobenzoic acid morpholide (13!-(132)-158)

In tetrahydrofuran (100 ml) and dichloromethane (100 ml), 3-nitrobenzoicacid (7.58 g) was dissolved. Then 1-hydroxybenzotriazole (6.74 g),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (9.57 g),and morpholine (9.47 g) were added to the solution. The mixture wasstirred at room temperature overnight. After the reaction was completed,chloroform was added to the solution. The mixture was washed with 1N-HClaqueous solution, 1N-NaOH aqueous solution, and distilled water. Theorganic layer was dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure, and the residue was purified bysilica gel column chromatography (Kieselgel 60=160 g, ethyl acetate) toobtain the above-captioned compound ( 13!-(132)-158) (9.62 g) as whitecrystals.

Melting point: 83.5°-85.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 3.4-4.1 (br,8H), 7.64 (t, 1H), 7.77 (dd, 1H), 8.29 (s, 1H), 8.31 (dd, 1H)

Example 84 Preparation of-3-aminobenzoic acid morpholide (13!-(133)-158)

The compound ( 13!-(132)-158) (8.63 g) prepared in Example 83 wasdissolved in ethanol (400 ml), and the solution was heated to 50° C. Tothe suspention, a solution of 10% Pd/C (2.25 g) in ethanol and hydrazinemonohydrate (4.4 ml) were added to the solution. The mixture was stirredfor 30 minutes. After the reaction was completed, the catalyst wasremoved by filtration through celite. The solution was concentrated, andthe residue was purified by silica gel column chromatography (Kieselgel60=120 g, ethyl acetate) to obtain the above-captioned compound (13!-(133)-158) (7.57 g) as a white solid.

Melting point: 72.0°-74.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 3.2-4.0 (br,8H), 6.6-6.8 (m, 3H), 7.17 (td, 1H)

Example 85 Preparation of 3-n-amylaminobenzoic acid morpholide (13!-(134)-158)

The compound ( 13!-(133)-158) (250 mg) prepared in Example 84 wasdissolved in ethanol (5 ml), and 10% Pd/C (25 mg) was added to thesolution. Under a hydrogen gas atmosphere, valeraldehyde (0.14 ml) wasadded to the mixture, and the mixture was stirred at room temperaturefor 3 hours. After the reaction was completed, the catalyst was removedby filtration through celite, and solution was concentrated. The residuewas purified by silica gel column chromatography (Kieselgel 60=15 g,hexane/ethyl acetate=1/1) to obtain the above-captioned compound (13!-(134)-158) (304 mg) as a white solid.

Melting point: 65.5°-67.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.93 (t, 3H),1.3-1.4 (m, 4H), 1.62 (quint, 2H), 3.11 (t, 2H), 3.3-4.0 (br, 8H), 4.59(bs, 1H), 6.1-6.5 (m, 3H), 7.17 (t, 1H)

Example 86 Preparation of 3-N-(4-methoxycarbonylphenyl)methyl!-n-amylaminobenzoic acid morpholide (13!-(135)-158')

The compound ( 13!-(134)-158) (257 mg) prepared in Example 85 wasdissolved in chloroform (7 ml), and methyl 4-bromomethylbenzoate anddiisopropylethylamine (1.6 ml ) were added to the solution. The mixturewas heated under reflux for 3 days. After the reaction was completed,the solution was concentrated. The residue was purified by silica gelcolumn chromatography (Kieselgel 60=39 g, ethyl acetate/hexane=1/1) toobtain the above-captioned compound ( 13!-(135)-158') (395 mg) ascolorless oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.90 (t, 3H), 1.3-1.4 (m, 4H), 1.66 (quint,2H), 3.42 (t, 2H), 3.2-3.9 (br, 8H), 3.90 (s, 3H), 4.59 (s, 2H),6.65-6.67 (m, 2H), 7.18 (t, 1H), 7.24 (d, 2H), 7.97 (d, 2H)

Example 87 Preparation of 3- N-(4-carboxyphenyl)methyl1-n-amylaminobenzoic acid morpholide ( 13!-(135)-158) (Compound No. 158)

The compound ( 13!-(135)-158') (354 mg) prepared in Example 86 wasdissolved in methanol (7.6 ml), and 1N NaOH aqueous solution (2 ml) wasadded to the solution. The mixture was stirred at room temperature for19 hours. After the reaction was completed, the solution was adjusted toapproximately pH 5 with 1N HCl aqueous solution, and extracted withethyl acetate. After the solution was dried over anhydrous sodiumsulfate, the solvent was evaporated under reduced pressure. The residuewas purified by silica gel column chromatography (Kieselgel 60=10 g,chloroform/methanol=10/1) to obtain the above-captioned compound (13!-(135)-158) (Compound No. 158) (327 mg) as light yellow foam.

Melting point: 64.0°-66.5° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.86 (t, 3H),1.2-1.4 (m, 4H), 1.61 (quint, 2H), 3.37 (t, 2H), 3.2-4.0 (br, 8H), 4.54(s, 2H), 6.56 (s, 1H), 6.61 (d, 2H), 7.13 (t, 1H), 7.20 (d, 2H), 7.95(d, 2H)

Example 88 Preparation of 4-chloro-3-nitrobenzoic acid morpholide (8!-(82)-41).

In thionyl chloride (10.0 ml), 4-chloro-3-nitrobenzoic acid (1.00 g) wasdissolved, and the solution was heated at 80° C. for 5 hours. Aftercooling, thionyl chloride was evaporated under reduced pressure todryness. The residue was dissolved in dichloromethane (10 ml), andmorpholine (0.87 ml) was added to the solution while cooling on ice.After stirring for 1 hour on ice, distilled water (10 ml) was added tothe solution. The whole was extracted with dichloromethane (20 ml). Theorganic layer was concentrated, and the residue was purified by silicagel column chromatography (Kieselgel 60=25 g, dichloromethane) to obtainthe above-captioned compound ( 8!-(82)-41) (0.966 g) as a light yellowsolid.

¹ H-NMR (500 MHz, CDCl₃) δ: 3.48 (bs, 2H), 3.80 (bs, 6H), 7.56 (dd, 1H),7.63 (d, 1H), 7.94 (d, 1H)

Example 89 Preparation of 4-n-amylamino-3-nitrobenzoic acid morpholide (8!-(83)-41)

Morpholine amide ( 8!-(82)-41) (0.60 g) prepared in Example 88 wasdissolved in a mixture of ethanol (5 ml) and THF (5 ml), and n-amylamine(0.52 ml) was added to the solution. The mixture was reacted at 90° C.for 19 hours. The solvent was evaporated, and the residue was extractedwith chloroform (100 ml) twice. After the organic layer was dried overanhydrous sodium sulfate, the organic layer was concentrated to obtainthe above-captioned compound ( 8!-(83)-41) (0.708 g) as a yellow solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.92 (t, 3H), 1.36-1.55 (m, 4H), 1.75(quint, 2H), 3.33 (td, 2H), 3.67 (bs, 4H), 3.71 (bs, 4H), 6.89 (d, 1H),7.58 (dd, 1H), 8.22 (bs, 1H), 8.29 (d, 1H)

Example 90 Preparation of 4-(N-n-amyl-N-methyl)amino-3-nitrobenzoic acidmorpholide ( 8!-(84)-41)

The compound ( 8!-(83)-41) (3.60 g) prepared in Example 89 was dissolvedin DMF (20 ml), and silver (I) oxide (12.0 g) and methyl iodide (15.0 g)were added to the solution. The mixture was stirred at room temperaturefor 3 days. The insolubles were filtered out through a glass filter G4.The filtrate was diluted with ethyl acetate (100 ml), and washed with 1NHCl aqueous solution. After the organic layer was concentrated, theresidue was purified by silica gel column chromatography Kieselgel 60=90g, hexane/ethyl acetate (from 3/1 to 2/1 to 1/1)! to obtain theabove-captioned compound ( 8!-(84)-41) (3.00 g) as orange oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.90 (t, 3H), 1.20-1.38 (m, 4H), 1.64(quint, 2H), 2.85 (s, 3H), 3.24 (t, 2H), 3.65 (bs, 4H), 3.71 (bs, 4H),7.04 (d, 1H), 7.48 (dd, 1H), 7.85 (d, 1H)

Example 91 Preparation of 3-amino-4-(N-n-amyl-N-methyl)aminobenzoic acidmorpholide ( 8!-(85)-41)

The nitro compound ( 8!-(84)-41) (1.06 g) prepared in Example 90 wasdissolved in a mixture of methanol (40 ml) and distilled water (40 ml),and sodium hydrosulfite (2.79 g) was added to the solution. The mixturewas stirred at room temperature for 1 hour. The reaction solution wasadjusted to pH 7 with sodium carbonate, and extracted with chloroform(100 ml). After the organic layer was dried over anhydrous sodiumsulfate, the residue was concentrated to obtain the above-captionedcompound ( 8!-(85)-41) (0.914 g) as colorless oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.88 (t, 3H), 1.25-1.35 (m, 4H), 1.49(quint, 2H), 2.62 (s, 3H), 2.84 (t, 3H), 3.68 (bs, 8H), 4.06 (bs, 2H),6.73 (dd, 1H), 6.77 (d, 1H), 6.98 (d, 1H)

Example 92 Preparation of 4-(N-n-amyl-N-methyl)amino-3-(4-methoxycarbonylphenyl)methyl!aminobenzoic acid morpholide (8!-(86)-41')

The aniline compound ( 8!-(85)-41) (366 mg) prepared in Example 91 wasdissolved in acetic acid (5.5 ml), and then4-methoxycarbonylbenzaldehyde (266 mg) was added to the solution. Themixture was stirred at room temperature for 1 hour. Borane-dimethylaminecomplex (83 mg) was added to the reaction solution, and the mixture wasstirred at the same temperature for 17 hours. Toluene was added to thereaction solution. The mixture was concentrated to remove acetic acid,and adjusted to pH 14 with 1N NaOH aqueous solution. The mixture wasextracted with chloroform, and the organic layer was concentrated.Further, benzene was added to the residue, and the mixture wasazeortopically distilled off. The resulting crude product was purifiedby preparative thin layer chromatography Merck 5717, benzene/ethylacetate=3/1) to obtain the above-captioned compound ( 8!-(86)-41') (150mg) as light yellow oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.86 (t, 3H), 1.20-1.33 (m, 4H), 1.48(quint, 2H), 2.63 (s, 3H), 2.84 (t, 3H), 3.10-3.90 (br, 8H), 3.91 (s,3H), 4.43 (d, 2H), 5.34 (t, 1H), 6.47 (d, 1H), 6.72 (dd, 1H), 7.02 (d,1H), 7.40 (d, 2H), 8.00 (d, 2H)

Example 93 Preparation of 4-(N-n-amyl-N-methyl)amino-3-(4-carboxyphenyl)methyl!aminobenzoic acid morpholide ( 8!-(86)-41)(Compound No. 41)

The aniline compound ( 8!-(85)-41) (5.45 g) prepared in Example 91 wasdissolved in toluene (210 ml). Then, diisopropylethylamine (23.0 g) andmethyl 4-bromomethylbenzoate (6.23 g) were added to the solution. Themixture was stirred at 90° C. for 48 hours under a nitrogen gasatmosphere. The reaction solution was concentrated, and the residue waspurified by silica gel column chromatography (Kieselgel 60=300 g,chloroform) to obtain a fraction (4.34 g) including the above compound (8!-(86)-41') as light yellow oil.

The resulting oil was dissolved in methanol (50 ml) and THF (50 ml), and1N NaOH aqueous solution (15 ml) was added to the solution. The mixturewas allowed to stand for 63 hours. After the reaction solution wasadjusted to pH 4 with 1N HCl aqueous solution, the solution wasextracted with chloroform (200 ml). After the organic layer wasconcentrated, the residue was purified by silica gel columnchromatography (Kieselgel 60=400 g, chloroform/methanol=15/1) to obtainthe above-captioned compound ( 8!-(86)-41) (Compound No. 41) (2.50 g) aslight yellow foam.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.86 (e, 3H), 1.22-1.35 (m, 4H), 1.48(quint, 2H), 2.61 (s, 3H), 2.85 (t, 2H), 3.20-3.85 (br, 8H), 4.46 (s,2H), 5.39 (br, 1H), 6.49 (d, 1H), 6.73 (dd, 1H), 7.03 (d, 1H), 7.43 (d,1H), 8.05 (d, 2H)

Example 94 Preparation of 2-chloroisonicotinic acid ( 9!-(92)-467)

Phosphorus oxychloride (220.7 g) was added to isonicotinic acid N-oxide(50.064 g), and the mixture was stirred on an oil bath at 120° C. for 7hours. The reaction mixture was slowly poured into ice water withvigorously stirring to precipitate light yellow crystals. The mixturewas adjusted to approximately pH 4 with 4N NaOH aqueous solution. Theresulting crystals were filtered out, washed with water, and dried byvacuum heating (60° C.) to obtain the above-captioned compound (9!-(92)-467) (37.845 g).

Melting point: 233.0°-234.0° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 7.82 (dd,1H), 7.84 (s, 1H), 8.61 (d, 1H), 13.91 (b, 1H)

Example 95 Preparation of 2-aminoisonicotinic acid ( 9!-(93)-467)

To the compound ( 9!-(92)-467) (31.5 g) prepared in Example 94, 25%ammonia aqueous solution (1500 ml) was added. The reaction was performedat 190° C. for 43 hours in an autoclave (pressure resistance=41 kg/cm²).The reaction mixture was concentrated to approximately 200 ml. Theresidue was adjusted to pH 0.8 with 6N HCl , and the precipitatedcrystals (unreactive starting compound=2.2 g) were filtered out. Thefiltrate was adjusted to pH 6 with sodium hydrogencarbonate. Theprecipitated crystals were filtered out, washed with water, and dried toobtain the above-captioned compound ( 9!-(93)-467) (21.5 g).

Melting point: >280° C. ¹ H-NMR (500 MHz, d₆ -DMSO) δ: 6.22 (s, 2H),6.87 (dd, 1H), 6.93 (s, 1H), 8.03 (d, 1H)

Example 96 Preparation of ethyl-2-aminoisonicotinate ( 9!-(93)-467')

Hydrogen chloride gas was blown into a suspension of the compound (9!-(93)-467) (5.2130 g) prepared in Example 95 in anhydrous ethanol (80ml) for 20 minutes, and the suspension was refluxed. The resultingyellow solution was stirred at room temperature for 20 hours, andconcentrated. The residue was diluted with chloroform. The solution waswashed with saturated sodium hydrogencarbonate aqueous solution andsaturated brine. The organic layer was dried over anhydrous sodiumsulfate, and concentrated. The resulting yellow crystals (6.1162 g) wererecrystallized from n-hexane/ethyl acetate to obtain the above-captionedcompound ( 9!-(93)-467') (4.7881 g).

Melting point: 119.0°-121.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 1.39 (t,3H), 4.37 (q, 2H), 4.60 (bs, 2H), 7.07 (s, 1H), 7.17 (dd, 1H), 8.18 (d,1H)

Example 97 Preparation of ethyl 2-valeramidoisonicotinate ( 9!-(94)-467)

The compound ( 9!-(93)-467') (2.0691 g) prepared in Example 96 wasdissolved in anhydrous pyridine (25 ml), and valeryl chloride (1.5 ml)was added dropwise to the solution with stirring and cooling on ice.After stirring and cooling on ice for 1 hour, the reaction solution waspoured into ice water. The solution was extracted with ethyl acetate,washed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated. The resulting light yellow oil (3.2548 g) waspurified by silica gel column chromatography (Kieselgel 60=160hexane/ethyl acetate=5/1) to obtain the above-captioned compound (9!-(94)-467) (3.0820 g) as white crystals.

Melting point: 46.0°-47.0° C. ¹ H-NHR (500 MHz, CDCl₃) δ: 0.96 (t, 3H),1.41 (t, 3H), 1.43 (sext, 2H), 1.74 (quint, 2H), 2.42 (t, 2H), 4.41 (q,2H), 7.60 (dd, 1H), 8.04 (bs, 1H), 8.38 (dd,1H), 8.74 (s, 1H)

Example 98 Preparation of 2-valeramidoisonicotinic acid ( 9!-(94)-467')

The compound ( 9!-(94)-467) (14.281 g) prepared in Example 97 wasdissolved in a mixture of methanol (114 ml) and tetrahydrofuran (114 ml). Then, 1N NaOH aqueous solution (114 ml) was added to the solution.The mixture was allowed to stand at room temperature for 1.5 hours. Thereaction solution was adjusted to pH 3 with 1N HCl aqueous solution. Theprecipitated crystals were filtered out, and washed with water. Thefiltrate was concentrated, and the precipitated crystals were washed.The precipitated crystals and the above crystals were combined, anddried by vacuum heating (60° C.) to obtain the above-captioned compound( 9!-(94)-467') (12.335 g) as white crystals.

Melting point: 255.0°-256.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.89 (t,3H), 1.32 (sext, 2H), 1.57 (quint, 2H), 2.42 (t, 2H), 7.49 (dd, 1H),8.46 (dd, 1H), 8.59 (s, 1H), 10.64 (s, 1H), 13.58 (b, 1H)

Example 99 Preparation of 2-valeramidoisonicotinic acid morpholide (9!-(94)-467")

The compound ( 9!-(94)-467') (2.4610 g) prepared in Example 98 wasdissolved in anhydrous dimethylformamide (DMF) (37 ml). Then,1-hydroxybenzotriazole (1.9477 g), N,N'-dicyclohexylcarbodiimide (2.9739g), and morpholine (1.3 ml) were added to the solution. The mixture wasstirred at room temperature for 16 hours. The insolubles were filteredout, and the filtrate was concentrated. The resulting residue wasdissolved in chloroform, washed with water and saturated brine, driedover anhydrous sodium sulfate, and concentrated to obtain yellowishbrown oil (7.4981 g). The crude oil was purified by silica gel columnchromatography (Kieselgel 60=230 g, chloroform/acetone=5/1) to obtainthe above-captioned compound ( 9!-(94)-467") (3.1756 g) as whitecrystals.

Melting point: 110.0°-112.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.88 (t,3H), 1.34 (sext, 2H), 1.64 (quint, 2H), 2.34 (t, 2H), 3.35 (bs, 2H),3.58 (bs, 2H), 3.71 (bs, 4H), 6.99 (dd, 1H), 8.12 (s, 1H), 8.17 (s, 1H),8.26 (d, 1H)

Example 100 Preparation of 2-N-(4-methoxycarbonylphenyl)methyl!valeramido!isonicotinic acid morpholide( 9!-(95)-467')

After oil of 60% NaH (3.160 g) was removed by washing with hexane,anhydrous dimethyl sulfoxide (DMSO) (120 ml) was added to the solution.The mixture was stirred at room temperature for 15 minutes. A solutionof the compound ( 9!-(94)-467") (15.342 g) prepared in Example 99 inanhydrous DMSO (120 ml) was added dropwise at room temperature to obtaina yellow suspension. To the suspension, a solution of methyl4-(bromomethyl)benzoate (14.476 g) in anhydrous DMSO (120 ml) was addeddropwise. After the resulting yellowish orange suspension was stirred atroom temperature for 2 hours, the reaction mixture was poured into icewater, and the whole was extracted with chloroform. The chloroform layerwas washed with water and saturated brine, dried over anhydrous sodiumsulfate, and concentrated to obtain yellowish brown oil (26.381 g). Thecrude oil was purified by silica gel column chromatography (Kieselgel60=1.3 kg, chloroform/acetone=15/1) to obtain the above-captionedcompound ( 9!-(95)-467') (17.277 g) as yellow oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.85 (t, 3H), 1.27 (sext, 2H), 1.63 (quint,2H), 2.33 (t, 2H), 3.22 (bs, 2H), 3.55 (bs, 2H), 3.75 (bs, 4H), 3.90 (s,3H), 5.20 (s, 2H), 7.15 (dd, 1H), 7.2-7.35 (b, 1H), 7.29 (d, 2H), 7.96(d, 2H), 8.53 (d, 1H)

Example 101 Preparation of 2-N-(4-carboxyphenyl)methyl!valeramido!isonicotinic acid morpholide (9!-(95)-467) (Compound No. 467)

The compound ( 9!-(95)-467') (0.9030 g) prepared in Example 100 wasdissolved in a mixture of methanol (7.2 ml) and tetrahydrofuran (7.2ml). Then, a solution of sodium hydrogencarbonate (0.2590 g) indistilled water (14.4 ml) was added to the solution. The mixture washeated under reflux on an oil bath at 100° C. for 8.5 hours. After thereaction solution was cooled, the solution was adjusted to pH 4 with 1NHCl aqueous solution (2.9 ml), and concentrated. The residue was dilutedwith chloroform. The solution was washed with saturated brine, driedover anhydrous sodium sulfate, and concentrated. The resulting yellowishbrown oil (0.6530 g) were purified by silica gel column chromatography(Kieselgel 60=33 g, chloroform/methanol=15/1) to obtain theabove-captioned compound ( 9!-(95)-467) (Compound No. 467) (0.4061 g) aswhite crystals.

Melting point: 152.0°-155.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.85 (t,3H), 1.27 (sext, 2H), 1.63 (quint, 2H), 2.34 (t, 2H), 3.24 (bs, 2H),3.56 (bs, 2H), 3.75 (s, 4H), 5.21 (s, 2H), 7.17 (t, 1H), 7.2-7.35 (b,1H), 7.31 (d, 2H), 7.98 (d, 2H), 8.54 (d, 1H)

Example 102 Preparation of 2-n-amylaminoisonicotinic acid morpholide (10!-(103)-535)

To 2-chloroisonicotinic acid morpholide (407 mg), n-amylamine (15 ml)was added, and the mixture was heated on an oil bath at 110° C. for 56hours under a nitrogen gas atmosphere. The reaction solution wasconcentrated, and washed with chloroform/water. After concentration, thecrude product was purified by silica gel column chromatographyLiChroprep Si 60=70 g, chloroform/methanol (from 60/1 to 40/1)! toobtain the above-captioned compound ( 10!-(103)-535) (349 mg) as lightyellow oil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.91 (t, 3H), 1.33-1.45 (m, 4H), 1.75(quint, 2H), 3.23 (q, 2H), 3.41 (bs, 2H), 3.77 (bs, 2H), 4.85 (bs, 4H),6.36 (s, 1H), 6.49 (dd, 1H), 8.10 (d, 1H)

Example 103 Preparation of 2-N-n-amyl-N-(4-methoxycarbonylphenyl)methyl!aminoisonicotinic acidmorpholide ( 10!-(104)-535')

The compound ( 10!-(103)-535) (4.58 g) prepared in Example 102 wasdissolved in toluene (100 ml). Then, diisopropylethylamine (21.3 g) andmethyl 4-bromomethylbenzoate (4.16 g) were added to the solution. Afterthe solution was degassed by sonication, the solution was heated on anoil bath at 110° C. for 24 hours under a nitrogen gas atmosphere. Thereaction solution was concentrated, and extracted with chloroform. Afterconcentration, the crude product was purified by silica gel columnchromatography (Kieselgel 60=100 g, ethyl acetate) to obtain a fraction(6.10 g) including the starting compound and the desired product.Further, the fraction was purified by silica gel column chromatographyKieselgel 60=240 g, hexane/ethyl acetate (from 1/2 to 1/1)! to obtainthe above-captioned compound ( 10!-(104)-535') (3.15 g) as colorlessoil.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.89 (t, 3H), 1.25-1.37 (m, 4H), 1.61(quint, 2H), 3.32 (bs, 2H), 3.45-3.50 (b, 4H), 3.74 (bs, 4H), 3.97 (s,3H), 4.83 (s, 2H), 6.37 (s, 1H), 6.49 (dd, 1H), 7.23 (d, 2H), 7.96 (d,2H), 8.19 (d, 1H)

Example 104 Preparation of 2-N-n-amyl-N-(4-carboxyphenyl)methyl!aminoisonicotinic acid morpholide (10!-(104)-535) (Compound No. 535)

The ester compound ( 10!-(104)-535) (5.12 g) prepared in Example 103 wasdissolved in a mixture of dioxane/water (1/1) (100 ml). Then, 1N NaOHaqueous solution (16 ml) was added to the solution. The mixture wasallowed to stand at room temperature for 6 hours. The reaction solutionwas adjusted to pH 2 with 1N HCl aqueous solution, and extracted withchloroform. After the reaction solution was concentrated, the crudeproduct was purified by silica gel column chromatography Kieselgel60=250 g, chloroform/methanol (from 15/1 to 10/1)! to obtain theabove-captioned compound ( 10!-(104)-535) (Compound No. 535) (4.34 g) aswhite crystals.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.88 (t, 3H), 1.28-1.37 (m, 4H), 1.63(quint, 2H), 3.33 (bs, 2H), 3.48 (t, 2H), 3.52 (bs, 2H), 3.74 (bs, 4H),4.85 (s, 2H), 6.41 (s, 1H), 6.50 (d, 1H), 7.27 (d, 2H), 7.99 (d, 2H),8.20 (d, 1H)

Example 105 Preparation of 4-(4-dimethylamino-3-nitrobenzene)sulfonyl!morpholine ( 11!-(113)-597)

In dioxane (120 ml), 4- (4-chloro-3-nitrobenzene)sulfonyl!morpholine (2!-(22)-596) (10.45 g) was dissolved. Then, triethylamine (9.50 ml) anddimethylamine hydrochloride (4.23 g) were added to the solution. Themixture was heated in a reactor made of pressure glass at 80° C. for 64hours. The reaction solution was extracted with chloroform (100 ml)three times. The organic layer was dried over anhydrous sodium sulfate,and the solvent was evaporated to obtain the above-captioned compound (11!-(113)-597) (10.7 g) as a yellow solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 3.02 (t-like, 4H), 3.06 (s, 6H), 3.76(t-like, 4H), 7.06 (d, 1H), 7.68 (dd, 1H), 8.15 (d, 1H)

Example 106 Preparation of 4-(3-amino-4-dimethylaminobenzene)sulfonyl!morpholine ( 11!-(114)-597)

The nitro compound ( 11!-(113)-597) (4.83 g) prepared in Example 105 wasdissolved in a mixture of THF (80 ml) and distilled water (80 ml). Then,sodium hydrosulfite (12.7 g) was added to the solution, and stirred atroom temperature for 2 hours. The reaction solution was made alkalinewith sodium hydrogencarbonate, and extracted with chloroform (100 ml)twice. The organic layer was dried over anhydrous sodium sulfate, andthe solvent was evaporated to obtain the above-captioned compound (11!-(114)-597) (3.23 g) as a light yellow solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 2.72 (s, 6H), 3.00 (t-like, 4H), 3.74(t-like, 4H), 4.07 (bs, 2H), 7.04 (m, 2H), 7.10 (dd, 1H)

Example 107 Preparation of 4-(4-dimethylamino-3-valeramidobenzene)sulfonyl!morpholine (11!-(115)-597)

The compound ( 11!-(114)-597) (2.73 g) prepared in Example 106 wasdissolved in anhydrous pyridine (80 ml), and the solution was cooled onice. Valeryl chloride (1.13 ml) was added dropwise to the solution. Themixture was stirred at the same temperature for 100 minutes, and stirredat room temperature for 30 minutes. The reaction mixture wasconcentrated, and the residue was extracted with chloroform (100 ml)twice. The organic layer was concentrated, and pyridine was removed byazeotropically distilling off with toluene. The resulting product waspurified by silica gel column chromatography (Kieselgel 60=250 g,chloroform/methanol=60/1) to obtain the above-captioned compound (11!-(115)-597) (1.97 g) as a white solid.

¹ H -NMR (500 MHz, CDCl₃) δ: 0.97 (t, 3H), 1.40-1.48 (m, 2H), 1.74(quint, 2H), 2.44 (t, 2H), 2.71 (s, 6H), 3.06 (t-like, 4H), 3.74(t-like, 4H), 7.23 (d, 1H), 7.41 (dd, 1H), 8.14 (bs, 1H), 8.73 (bs, 1H)

Example 108 Preparation of 4- 4-dimethylamino-3-N-(4-methoxycarbonylphenyl)methyl!valeramidobenzene!sulfonyl!morpholine (11!-(116)-597')

NaH (0.36 g) (50% content) was suspended in DMSO (20 ml). A solution ofthe compound ( 11!-(115)-597) (1.97 g) prepared in Example 107 in DMSO(23 ml) was added to the suspension. After 15 minutes, a solution ofmethyl 4-bromomethylbenzoate (1.50 g) in DMSO (20 ml) was added to themixture, and the mixture was stirred at room temperature for 1.5 hours.The reaction solution was poured into 1N HCl aqueous solution (100 ml),and the whole was extracted with ethyl acetate (100 ml) twice. Theorganic layer was concentrated, and the resulting crude product waspurified by silica gel column chromatography (Kieselgel 60=250 g,chloroform/methanol=80/1) to obtain the above-captioned compound (11!-(116)-597') (2.26 g) as a white solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.86 (t, 3H), 1.20-1.33 (m, 2H), 1.62-1.69(m, 2H), 1.98 (td, 1H), 2.31 (td, 1H), 2.50-2.60 (bm, 2H), 2.60-2.70(bm, 2H), 2.98 (s, 6H), 3.55-3.63 (m, 4H), 3.87 (s, 3H), 4.04 (d, 1H),5.80 (d, 1H), 6.87 (d, 1H), 7.00 (d, 1H), 7.21 (d, 2H), 7.51 (dd, 1H),7.89 (d, 2H)

Example 109 Preparation of 4- 3-N-(4-carboxyphenyl)methyl!valeramido-4-dimethylaminobenzene!sulfonyl!morpholine( 11!-(116)-597) (Compound No. 597)

The methyl ester compound ( 11!-(116)-597') (2.20 g) prepared in Example108 was dissolved in a mixture of THF (25 ml) and methanol (25 ml).Then, 1N NaOH aqueous solution was added to the solution. The mixturewas allowed to stand for 25.5 hours. The reaction solution was adjustedto pH 1 with 1N HCl aqueous solution, and the solvent was evaporated. Tothe residue, 1N HCl aqueous solution was added, and the whole wasextracted with dichloromethane (40 ml) twice. The resulting crudeproduct was purified by silica gel column chromatography (Kieselgel60=125 g, from chloroform/methanol=30/1 to chloroform/methanol=20/1 tochloroform/methanol=10/1) to obtain the above-captioned compound (11!-(116)-597) (Compound No. 597) (1.84 g) as a white solid.

¹ H-NMR (500 MHz, CDCl₃) δ: 0.86 (t, 3H), 1.20-1.33 (m, 2H), 1.61-1.71(m, 2H), 2.10 (td, 1H), 2.32 (td, 1H), 2.50-2.60 (bm, 2H), 2.60-2.70 (m,2H), 2.99 (s, 6H), 3.60 (t-like, 4H), 4.07 (d, 1H), 5.79 (d, 1H), 6.88(d, 1H), 7.01 (d, 1H), 7.23 (d, 2H), 7.52 (dd, 1H), 7.94 (d, 2H)

Example 110 Preparation of 4-dimethylamino-3-N-(4-methoxycarbonylphenyl)methyl!aminobenzoic acid morpholide (12!-(121)-225)

In acetic acid (15 ml), 4-dimethylamino-3-aminobenzoic acid morpholide (5!-(55)-591) (1.00 g) was dissolved. Then, 4-methoxycarbonylbenzaldehyde(691 mg) was added. The solution became yellow immediately. The solutionwas stirred at room temperature for 4 hours. Then dimethylamine-boranecomplex (260 mg) was added to the solution, the mixture was stirred atroom temperature for 1 hour. After the reaction was completed, distilledwater was added to the solution. The solution was extracted with ethylacetate, washed with saturated sodium hydrogencarbonate aqueous solutionand distilled water, and dried over anhydrous sodium sulfate. Thesolvent was evaporated under reduced pressure, and the residue waspurified by silica gel column chromatography (Kieselgel 60=60 g,hexane/ethyl acetate=1/1) to obtain the above-captioned compound (12!-(121)-225) (1.44 g) as a white solid.

Melting point: 109.5°-110.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 2.69 (s,6H), 3.0-3.9 (br, 8H), 3.91 (s, 3H), 4.44 (d, 1H), 5.21 (t, 1H), 6.47(d, 1H), 6.74 (dd, 1H), 7.02 (d, 1H), 7.44 (d, 2H), 8.00 (d, 2H)

Example 111 Preparation of 4-dimethylamino-3-1-(4-methoxycarbonylphenyl)methyl-3-propyl!ureidobenzoic acid morpholide( 12!-(122)-225')

The compound ( 12!-(121)-225) (250 mg) prepared in Example 110 wasdissolved in toluene (5 ml). Then, n-propyl isocyanate (0.118 ml) wasadded dropwise. The mixture was refluxed for 2 days. After the reactionwas completed, the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (LiChroprep Si60=25 g, hexane/ethyl acetate=3/20) to obtain the above-captionedcompound ( 12!-(122)-225') (239 mg) as a white solid.

Melting point: 141.0°-142.0° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.84 (t,3H), 1.45 (sext, 2H), 2.90 (s, 6H), 3.0-3.8 (br, 10H), 3.88 (s, 3H),4.2-4.4 (br, 1H), 4.62 (t, 1H), 5.4-5.7 (br, 1H), 6.64 (d, 1H), 6.98 (d,1H), 7.22 (d, 2H), 7.28 (dd, 1H), 7.85 (d, 2H)

Example 112 Preparation of 4-dimethylamino-3-1-(4-carboxyphenyl)methyl-3-propyl!ureidobenzoic acid morpholide (12!-(122)-225) (Compound No. 225)

The ester compound ( 12!-(122)-225') (102 mg) prepared in Example 111was dissolved in methanol (2 ml), and 1N NaOH aqueous solution (0.5 ml)was added to the solution. The mixture was stirred at room temperaturefor 2 days. After the reaction was completed, the solution was adjustedto pH 2-3 with 1N HCl aqueous solution. The solution was extracted withethyl acetate, and dried over anhydrous sodium sulfate. The solvent wasevaporated under reduced pressure. The residue was purified bypreparative thin layer chromatography (Merck 13872,chloroform/methanol=20/3), and further recrystallized fromchloroform/hexane to obtain the above-captioned compound (12!-(122)-225) (Compound No. 225) (66 mg) as white plate crystals.

Melting point: 127.0°-130.5° C. ¹ H-NMR (500 MHz, CDCl₃) δ: 0.76 (t,3H), 1.37 (sext, 2H), 2.82 (s, 6H), 2.9-3.8 (br, 10H), 4.0-4.3 (br, 4.66(t, 1H), 5.4-5.7 (br, 1H), 6.59 (d, 1H), 6.90 (d, 1H), 7.16 (d, 2H),7.21 (dd, 1H), 7.80 (d, 2H)

Example 113 Acute Toxicity

Five-week-old ICR female mice (5 mice per group) were bred foracclimation for a week. Then, the compounds of the present inventionwere dissolved or dispersed in an aqueous solution of 0.5%methylcellulose, and orally administered to the mice in a single dosage(500 mg/kg). The number of deaths was observed for 6 days after theadministration. The results are shown in Table 22.

                  TABLE 22                                                        ______________________________________                                        Compound No.                                                                             Number of deaths/number of survivals                               ______________________________________                                        1          0/5                                                                41         0/5                                                                90         0/5                                                                158        0/5                                                                184        0/5                                                                225        0/5                                                                252        0/5                                                                278        0/5                                                                372        0/5                                                                467        0/5                                                                535        0/5                                                                585        0/5                                                                586        0/5                                                                587        0/5                                                                591        0/5                                                                592        0/5                                                                593        0/5                                                                594        0/5                                                                595        0/5                                                                596        0/5                                                                598        0/5                                                                599        0/5                                                                604        0/5                                                                ______________________________________                                    

Example 114 Binding to Receptors

In this Example, the affinity to the angiotensin II receptor subtype 1or subtype 2 was evaluated by a binding assay in accordance with themethod described in Biochem. Pharmacol., 33, 4057-4062 (1984).

Specifically, the measurement of the total binding in the presence ofeach drug was performed as follows:

A mixture (final volume=0.25 ml) of a drug in a given concentration (thedrug was dissolved in DMSO, and diluted to a double volume with a bufferattached to a drug discovery system to prepare sample for the assay;0.025 ml), a tracer (0.025 ml), and receptors (0.2 ml) was incubated inthe case of the angiotensin II receptor subtype 1 (AT₁), at roomtemperature for 3 hours, and in the case of the subtype 2 (AT₂), at 37°C. for 1 hour!. Then, the reaction mixture was filtered with suction(GF/C filter was used in AT₁, and GF/B filter was used in AT₂). Thefilter papers after filtration with suction (the tracer bound to thereceptors) were counted by a γ-well counter (ARC-500, Aloka). Thenon-specific bindings were measured by repeating the above method,except that a large excess amount of a displacer was added. The specificbinding of the drug in the given concentration was calculated bysubtracting the non-specific binding from the total binding,respectively.

In AT₁ and AT₂, the percentages to inhibit the bindings of radioactiveligands (tracer) to receptors by the drugs to be tested (IC₅₀ value ofconcentration to show 50% inhibition, or binding inhibition % in 100 μM)were measured, using the drugs to be tested and control drugs in thegiven concentration. The results are shown in Table 23.

                  TABLE 23                                                        ______________________________________                                                           Binding                                                                       inhibition %                                               Compound  IC.sub.50      in 100 μM                                         No.       AT.sub.1 (nM)  AT.sub.1                                                                             AT.sub.2                                      ______________________________________                                         1                       33     0                                              41                      26     0                                              75                      15     0                                              90                      30     0                                             158                      18     0                                             184                      0      0                                             225                      4      0                                             252                      34     0                                             278                      4      0                                             372                      2      0                                             467                      16     0                                             535       3800                  0                                             585       1700                  0                                             586       1200                  0                                             587       7900                  0                                             591                      35     0                                             592       4900                  0                                             593                      36     0                                             594       32000                 0                                             595                      41     0                                             596                      22     0                                             597                      0      0                                             598                      36     0                                             599                      38     0                                             604                      15     0                                             DuP753    20                    0                                             In AT.sub.1,                                                                  receptor       from adrenal glands in rabbits                                 tracer         .sup.3 H-angiotensin II                                        control drug   DuP753                                                         (displacer)    DuP753                                                         In AT.sub.2,                                                                  receptor       from cerebellar cortex in bovine                               tracer         .sup.125 I-Tyr.sup.4 -angiotensin II                           control drug   angiotensin II (human)                                         (displacer)    angiotensin II (human)                                         ______________________________________                                    

As clear from Table 23, IC₅₀ values of the compounds of the presentinvention to the angiotensin II subtype 1 receptor were not less than1000 nM, whereas IC₅₀ value of DuP753 used as a control substance was 20nM. Therefore, it can be said that the compounds of the presentinvention having IC₅₀ values of not less than 1000 nM exhibit noinhibitory effect on the subtype 1 receptor. The fact that the compoundsof the present invention exhibit no binding activity to the subtype 1receptor shows that such compounds are completely different fromconventional ACE inhibitors or angiotensin II antagonists in actionmechanism.

Example 115 Action to Depress Blood Pressure

The compounds of the present invention and the reference substance wereforcedly administered per os to kidney disease model rats, and theaction to depress blood pressure was observed. The kidney disease modelrats were prepared by ligature of branches of renal artery in accordancewith the conventional method, that is, the left hilum renalis ofSprague-Dawley female rats was exposed under anesthesia, and one of foursecondary branches of renal artery was left unligated, while theremaining three branches were ligated, respectively. After a week, thehilum renalis (artery, vein, and ureter) of the right kidney werefurther ligated to thereby prepare the rats whose renal function waslowered to approximately 1/8 of the normal function. Each groupconsisted of eight rats. The drugs to be tested (20 mg/kg) wereadministered to each administering group, and only water wasadministered to control group. After two days from the administration,the systolic blood pressure was measured by the tail cuff method using ablood pressure measuring apparatus (UR5000; Ueda). The average of theblood pressures is shown in Table 24.

                  TABLE 24                                                        ______________________________________                                        Compound No. Blood pressure (mmHg)                                            ______________________________________                                         1           196                                                               41          195                                                               90          194                                                              158          190                                                              184          195                                                              225          195                                                              252          200                                                              278          198                                                              372          190                                                              467          200                                                              535          195                                                              585          196                                                              586          198                                                              587          201                                                              591          199                                                              592          202                                                              593          200                                                              594          194                                                              595          198                                                              596          198                                                              598          202                                                              599          200                                                              604          200                                                              control      203                                                              DuP753       135                                                              ______________________________________                                    

In comparison with the control group, the reference substance (DuP753)clearly showed the action to depress the blood pressure. On thecontrary, influence on the blood pressure was not substantially shown inthe compounds of this invention.

Example 116 Renal Function Indicator Value (action to kidney diseases)

The kidney disease model rats were prepared as in Example 115.Twenty-five groups (8 rats per group) were sleeked in a manner so thatthere were no major differences between each group in the serumcreatinine value and the urea nitrogen value indicating renal function.The rats in each group were allowed to freely take up feed and water. Tothe rats in the administering group, the compounds of this invention orthe reference substance (DuP753) were forcedly administered per os atthe dose of 20 mg/kg/day every day. To the rats in the control group,only water was forcedly administered per as every day. After two weeks,0.2 ml of blood was collected from the carotid artery of the rat underanesthesia, and centrifuged to obtain serum. Using 25 μl of the serum,serum creatinine (Scr) was measured by a creatinine analyticalinstrument (Beckman). Using 10 μl of the serum, urea nitrogen (BUN) wasmeasured by a BUN analytical instrument (Beckman). Creatinine clearancewas evaluated as follows:

After serum creatinine measurement, rats were placed in urinarymetabolic cages for 24 hours to collect urine. Urinary creatineconcentration (Ucr) was measured by a creatinine analytical instrument,and total volume of urination (Uvol) was also measured. Creatinineclearance (CCr) was calculated by the following formula: ##EQU1## Theresults are shown in Table 25.

                  TABLE 25                                                        ______________________________________                                                                Urea    Creatinine                                    Compound   Creatinine   nitrogen                                                                              clearance                                     No.        mg/dl        mg/dl   ml/min                                        ______________________________________                                         1         1.6          75      0.34                                           41        1.6          72      0.36                                           90        1.5          70      0.38                                          158        1.7          74      0.37                                          184        1.5          70      0.38                                          225        1.8          73      0.25                                          252        1.7          73      0.28                                          278        1.8          73      0.36                                          372        1.7          72      0.36                                          467        1.8          74      0.25                                          535        1.5          72      0.38                                          585        1.6          72      0.35                                          586        1.7          76      0.33                                          587        1.7          77      0.34                                          591        1.6          76      0.33                                          592        1.7          76      0.33                                          593        1.6          80      0.31                                          594        1.7          77      0.30                                          595        1.5          73      0.38                                          596        1.6          78      0.34                                          598        1.6          80      0.35                                          599        1.5          73      0.35                                          604        1.8          75      0.28                                          control    2.0          100     0.20                                          DuP753     1.6          80      0.32                                          ______________________________________                                    

When the compounds of the present invention were administered, the serumcreatinine value and the urea nitrogen value which increase withaggravation of renal failure clearly became lower values and creatinineclearance indicating renal function was clearly improved in comparisonwith the control substance. The pharmacological effects were comparableto those of the reference substance, and it was shown that the compoundsof the present invention do not substantially exhibit conventionalangiotensin II receptor antagonism and blood pressure depression action,but improve kidney diseases.

Example 117 Action to Survival Time of Kidney Diseased Animals

The kidney disease model rats were prepared as in Example 115.Twenty-five groups (8 rats per group) were prepared in a manner so thatthere was no major difference between the groups in the serum creatininevalue and the urea nitrogen value indicating renal function. The rats ineach group were allowed to freely take up feed and water. To the rats inthe administering group, the compounds of the present invention or thereference substance (DuP753) were forcedly administered per os at thedose of 20 mg/kg/day every day. To the rats in he control group, onlywater was forcedly administered per os every day. If kidney diseases areaggravated, the rat will die of uremia. Thus, the survival time wasobserved as comprehensive indication of the improvement effect on thekidney diseases. The results are shown in Table 26. The observationperiod was eight weeks. Thus if all rats survived, the average survivaltime is eight weeks and it is an upper limit.

                  TABLE 26                                                        ______________________________________                                        Compound No. Average survival time (weeks)                                    ______________________________________                                         1           7.1                                                               41          7.6                                                               90          7.6                                                              158          7.2                                                              184          7.6                                                              225          7.0                                                              252          7.0                                                              278          7.0                                                              372          7.6                                                              467          7.0                                                              535          7.6                                                              585          7.3                                                              586          6.8                                                              587          7.0                                                              591          7.3                                                              592          7.0                                                              593          7.1                                                              594          6.5                                                              595          7.6                                                              596          6.0                                                              598          7.2                                                              599          7.0                                                              604          7.0                                                              control      5.0                                                              DuP753       6.9                                                              ______________________________________                                    

The compounds of the present invention clearly prolonged the survivaltime of the kidney disease model rats. The effect was comparable orsuperior to that of the reference substance. It was shown that thecompounds of this invention do not substantially exhibit knownangiotensin II receptor antagonism and blood pressure depression action,but prolonged the survival time of the rats which died of kidneydiseases

Example 118

The Compound No. 1 (10 mg), lactose (36 mg), corn starch (150 mg),microcrystalline cellulose (29 mg), and magnesium stearate (5 mg) weremixed, and tableted to prepare tablets (230 mg/tablet).

Although the present invention has been described with reference tospecific embodiments, various changes and modifications obvious to thoseskilled in the art are deemed to be within the spirit, scope, andconcept of the invention.

We claim:
 1. A benzene derivative of the formula (I): ##STR16## whereinR₂ is a hydroxyl, OR₂₂, three-membered to seven-membered saturatedcycloaliphatic amino group which may be interrupted by one or morenitrogen, oxygen or sulfur atoms, --NHR²³, --N(R²⁴)₂ or --NH₂ group; R⁷is --CO--; R¹² is --R¹¹ --R⁵ ; R¹¹ is --NH--, --N(R²⁶)--,--N(C(═O)R₂₇)--, --N(C(═O)NH₂)-- or --N(C(═O)NHR²⁸)--; R¹³ is a hydrogenatom, alkyl of 1 to 6 carbon atoms or haloalkyl of 1 to 4 carbon atoms;Z is N; R⁵ is --CH₂ C₆ H₄ COOH, --CH₂ C₆ H₄ COOR³¹, --CH₂ C₆ H₄ OH,--CH₂ C₆ H₄ OR³², --CH₂ C₆ H₄ NH₂, --CH₂ C₆ H₄ N(R³³)₂, --CH₂ C₆ H₄-azole or --CH₂ C₆ H₄ NHR³⁴ group; R²², R²³, R₂₄, R²⁶, R²⁷, R²⁸, R³¹,R³², R³³ and R³⁴, are independently an alkyl of 1 to 6 carbon atoms orhaloalkyl group of 1 to 6 carbon atoms, or a salt thereof.
 2. A benzenederivative according to claim 1 wherein R¹ is a hydrogen atom, alkyl of1 to 5 carbon atoms, haloalkyl of 1 to 5 carbon atoms, or --NHR₂₁group;! R₂ is a hydroxyl, OR²², three-membered to six-membered saturatedcycloaliphatic amino group which may be interrupted by one or morenitrogen, oxygen or sulfur atoms, --NHR²³, --N(R²⁴)₂ ,! or --NH₂ group;R⁴ is a hydrogen atom, alkyl of 1 to 4 carbon atoms, or --C(═O)R²⁵group; R⁷ is a --CO-- or --SO₂ --; R⁸ is a --CO-- or single bond;! R¹²is --R¹¹ --R⁵ ; R¹¹ is --N(R⁵)--,!--NH--, --O--,! --N(R²⁶)--,--N(C(═O)R²⁷)--, --N(C(═O)NH₂)-- ,! or --N(C(═O)NHR²⁸)--; R¹³ is ahydrogen atom, alkyl of 1 to 4 carbon atoms ,! or haloalkyl of 1 to 4carbon atoms , --NHC(═O)(CH_(2m) C₆ H₅, --NHC(═O)R²⁹, --NHC(═O)CH(C₆H₅)₂, --NH₂, --NHR³⁰, or --(CH₂)_(n) C₆ H₅ ; Z is C, CH, or N; A is CHor N!; R₅ is a hydrogen atom,! --CH₂ C₆ H₄ COOH, --CH₂ C₆ H₄ COOR³¹,--CH₂ C₆ H₄ OH, --CH₂ C₆ H₄ OR³², --CH₂ C₆ H₄ NH₂, --CH₂ C₆ H₄ N(R³³)₂,--CH₂ C₆ H₄ -azole ,! or --CH₂ C₆ H₄ NHR³⁴ , or --CH₂ C₆ H₄ C₆ H₄ R¹⁴ !group; R¹⁴ is an 1H-tetrazole or --COOH group; R²¹,! R²², R²³, R²⁴,R²⁵,! R²⁶, R²⁷, R²⁸, R²⁹, R³⁰,! R³¹, R³², R³³, and R³⁴, areindependently an alkyl of 1 to 4 carbon atoms or haloalkyl group of 1 to4 carbon atoms; m is 0 or an integer of 1 to 4; n is 0 or an integer of1 to 4; t is 0 or 1, with the proviso that when Z is N, R⁵ is a hydrogenatom, --CH₂ C₆ H₄ COOH, --CH₂ C₆ H₄ COOR³¹, --CH₂ C₆ H₄ OH, --CH₂ C₆ H₄OR³², --CH₂ C₆ H₄ NH₂, --CH₂ C₆ H₄ N(R³³)₂, --CH₂ C₆ H₄ -azole, or --CH₂C₆ H₄ NHR³⁴ group,! or a salt thereof.
 3. A benzene derivative accordingto claim 1 wherein R⁵ is --CH₂ C₆ H₄ COOH, or a salt thereof.
 4. Abenzene derivative according to claim 1 wherein R⁵ is --CH₂ C₆ H₄-4-COOH, or a salt thereof.
 5. A pharmaceutical composition comprising abenzene derivative of the formula (I): ##STR17## wherein R₂ is ahydroxyl, OR₂₂, three-membered to seven-membered saturatedcycloaliphatic amino group which may be interrupted by one or morenitrogen, oxygen or sulfur atoms, --NHR₂₃, --N(R₂₄)₂ or --NH₂ group; R⁷is --CO--; R¹² is --R¹¹ --R⁵ ; R¹¹ is --NH--, --N(R²⁶)--,--N(C(═O)R₂₇)--, --N(C(═O)NH₂)-- or --N(C(═O)NHR²⁸)--; R¹³ is a hydrogenatom, alkyl of 1 to 6 carbon atoms or haloalkyl of 1 to 4 carbon atoms;Z is N; R₅ is --CH₂ C₆ H₄ COOH, --CH₂ C₆ H₄ COOR³¹, --CH₂ C₆ H₄ OH,--CH₂ C₆ H₄ OR.sub.³², --CH₂ C₆ H₄ NH₂, --CH₂ C₆ H₄ N(R³³)₂, --CH₂ C₆ H₄-azole or --CH₂ C₆ H₄ NHR³⁴ group; R²², R²³, R²⁴, R²⁶, R²⁷, R²⁸, R³¹,R³², R³³ and R³⁴, are independently an alkyl of 1 to 6 carbon atoms orhaloalkyl group of 1 to 6 carbon atoms, or a pharmaceutically acceptablesalt thereof, and a pharmaceutically acceptable carrier.
 6. Thepharmaceutical composition of claim 5, wherein R² is a hydroxyl, OR²²,three-membered to six-membered saturated cycloaliphatic amino groupwhich may be interrupted by one or more nitrogen, oxygen or sulfuratoms, --NHR²³, --N(R²⁴)₂ or --NH₂ groups; R¹² is --R¹¹ --R⁵ ; R¹¹ is--NH--, --N(R²⁶)--, --N(C(═O)R²⁷)--, --N(C(═O)NH₂)-- or--N(C(═O)NHR²⁸)--; R¹³ is a hydrogen atom, alkyl of 1 to 4 carbon atomsor haloalkyl of 1 to 4 carbon atoms; R₅ is --CH₂ C₆ H₄ COOH, --CH₂ C₆ H₄COOR³¹ ; --CH₂ C₆ H₄ OH, --CH₂ C₆ H₄ OR³², --CH₂ C₆ H₄ NH₂, --CH₂ C₆ H₄N(R³³)₂, --CH₂ C₆ H₄ -azole or --CH₂ C₆ H₄ NHR³⁴ group; R²², R²³, R²⁴,R²⁶, R²⁷, R²⁸, R³¹, R³², R³³ and R³⁴, are independently an alkyl of 1 to4 carbon atoms or haloalkyl group of 1 to 4 carbon atoms, or apharmaceutically acceptable salt thereof.
 7. The pharmaceuticalcomposition of claim 5, wherein R⁵ is --CH₂ C₆ H₄ COOH, or apharmaceutically acceptable salt thereof.
 8. The pharmaceuticalcomposition of claim 5, wherein R⁵ is --CH₂ C₆ H₄ -4-COOH, or apharmaceutically acceptable salt thereof.
 9. A method for treatingkidney disease comprising administering to a patient in need oftreatment an effective amount of a composition comprising a benzenederivative of the formula ##STR18## wherein R₂ is a hydroxyl, OR²²,three-membered to seven-membered saturated cycloaliphatic amino groupwhich may be interrupted by one or more nitrogen, oxygen or sulfuratoms, --NHR²³, --N(R²⁴)₂ or --NH₂ group; R⁷ is --CO--; R¹² is --R¹¹--R⁵ ; R¹¹ is --NH--, --N(R²⁶)--, --N(C(═O)R²⁷)--, --N(C(═O)NH₂)-- or--N(C(═O)NHR²⁸)--; R¹³ is a hydrogen atom, alkyl of 1 to 6 carbon atomsor haloalkyl of 1 to 4 carbon atoms; Z is N; R₅ is --CH₂ C₆ H₄ COOH,--CH₂ C₆ H₄ COOR³¹, --CH₂ C₆ H₄ OH, --CH₂ C₆ H₄ OR³², --CH₂ C₆ H₄ NH₂,--CH₂ C₆ H₄ N(R³³)₂, --CH₂ C₆ H₄ -azole or --CH₂ C₆ H₄ NHR³⁴ group; R²²,R²³, R²⁴, R²⁶, R²⁷, R²⁸, R³¹, R³², R³³ and R³⁴, are independently analkyl of 1 to 6 carbon atoms or haloalkyl group of 1 to 6 carbon atoms,or a pharmaceutically acceptable salt thereof.
 10. The method of claim9, wherein R² is a hydroxyl, OR²², three-membered to six-memberedsaturated cycloaliphatic amino group which may be interrupted by one ormore nitrogen, oxygen or sulfur atoms, --NHR²³, --N(R²⁴)₂ or --NH₂groups; R¹² is --R¹¹ --R⁵ ; R¹¹ is --NH--, --N(R²⁶)--, --N(C(═O)R²⁷)--,--N(C(═O)NH₂)-- or --N(C(═O)NHR²⁸)--; R¹³ is a hydrogen atom, alkyl of 1to 4 carbon atoms or haloalkyl of 1 to 4 carbon atoms; R₅ is --CH₂ C₆ H₄COOH, --CH₂ C₆ H₄ COOR³¹, --CH₂ C₆ H₄ OH, --CH₂ C₆ H₄ OR³², --CH₂ C₆ H₄NH₂, --CH₂ C₆ H₄ N(R³³)₂, --CH₂ C₆ H₄ -azole or --CH₂ C₆ H₄ NHR³⁴ group;R²², R²³, R²⁴, R²⁶, R²⁷, R²⁸, R³¹, R³², R³³ and R³⁴, are independentlyan alkyl of 1 to 4 carbon atoms or haloalkyl group of 1 to 4 carbonatoms, or a pharmaceutically acceptable salt thereof.
 11. The method ofclaim 9, wherein R⁵ is --CH₂ C₆ H₄ COOH, or a pharmaceuticallyacceptable salt thereof.
 12. The method of claim 9, wherein R⁵ is --CH₂C₆ H₄ -4-COOH, or a pharmaceutically acceptable salt thereof.